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Chen D. Targeted Therapy Evolution from Defining a Sub-population to Crossing Multi-indications. Adv Pharm Bull 2024; 14:737-744. [PMID: 40190666 PMCID: PMC11970494 DOI: 10.34172/apb.43306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 08/12/2024] [Accepted: 09/08/2024] [Indexed: 04/09/2025] Open
Abstract
Purpose It tends not only to shed lights on an emerging classification framework of disease according to the shared molecular pathogenesis across various organs/tissues, but also to inspire more efficient paradigms of pharmaceutic innovation in a broader medical perspective. Methods Literature review and re-thinking. Results This article has sorted out an updated profile of the outstanding targeted medications with an extending list of clinical indications in oncology and beyond. Conclusion Pharmaceutic development can be processed in a less risky and more affordable manner through drug repurpose or tissue agnostic approval.
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Affiliation(s)
- Daohong Chen
- Research Institute, Changshan Biochemical Pharmaceutical, North Head of Yinchuan Street, Zhengding New District, Shijiazhuang, Hebei, China, 050800
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Arvanitakis K, Koufakis T, Kalopitas G, Papadakos SP, Kotsa K, Germanidis G. Management of type 2 diabetes in patients with compensated liver cirrhosis: Short of evidence, plenty of potential. Diabetes Metab Syndr 2024; 18:102935. [PMID: 38163417 DOI: 10.1016/j.dsx.2023.102935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 12/16/2023] [Accepted: 12/21/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND AND AIMS Treatment of type 2 diabetes (T2D) in patients with compensated cirrhosis is challenging due to hypoglycemic risk, altered pharmacokinetics, and the lack of robust evidence on the risk/benefit ratio of various drugs. Suboptimal glycemic control accelerates the progression of cirrhosis, while the frequent coexistence of nonalcoholic fatty liver disease (NAFLD) with T2D highlights the need for a multifactorial therapeutic approach. METHODS A literature search was performed in Medline, Google Scholar and Scopus databases till July 2023, using relevant keywords to extract studies regarding the management of T2D in patients with compensated cirrhosis. RESULTS Metformin, sodium-glucose co-transporter-2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) are promising treatment options for patients with T2D and compensated liver cirrhosis, offering good glycemic control with minimal risk of hypoglycemia, while their pleiotropic actions confer benefits on NAFLD and body weight, and decrease cardiorenal risk. Sulfonylureas cause hypoglycemia, thus should be avoided, while in specific studies, dipeptidyl peptidase-4 inhibitors have been correlated with increased risk of decompensation and variceal bleeding. Despite the benefits of thiazolidinediones in nonalcoholic steatohepatitis, concerns about edema and weight gain limit their use in compensated cirrhosis. Insulin does not exert hepatotoxic effects and can be administered safely in combination with other drugs; however, the risk of hypoglycemia should be considered. CONCLUSIONS The introduction of new hepatoprotective diabetes drugs into clinical practice, including tirzepatide, SGLT2i, and GLP-1 RA, sets the stage for future trials to investigate the ideal therapeutic regimen for people with T2D and compensated cirrhosis.
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Affiliation(s)
- Konstantinos Arvanitakis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636, Thessaloniki, Greece; Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636, Thessaloniki, Greece
| | - Theocharis Koufakis
- Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642, Thessaloniki, Greece
| | - Georgios Kalopitas
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636, Thessaloniki, Greece; Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636, Thessaloniki, Greece
| | - Stavros P Papadakos
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 54636, Thessaloniki, Greece
| | - Georgios Germanidis
- Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636, Thessaloniki, Greece; Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636, Thessaloniki, Greece.
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Mariam Z, Niazi SK. Glucagon-like peptide agonists: A prospective review. Endocrinol Diabetes Metab 2024; 7:e462. [PMID: 38093651 PMCID: PMC10782143 DOI: 10.1002/edm2.462] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 11/03/2023] [Accepted: 11/19/2023] [Indexed: 01/13/2024] Open
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising therapeutic options for addressing Type-2 diabetes, obesity, and related conditions. Among these, semaglutide, tirzepatide, liraglutide etc., all notable GLP-1RA, have gained attention owing to their favourable pharmacological properties and clinical efficacy. AIMS This comprehensive review aims to provide a detailed analysis of both the currently available GLP-1RAs in the market and those undergoing clinical trials. The focus is on examining their mechanism of action, pharmacokinetics, efficacy in glycemic control and weight management, safety profile, and potential applications. MATERIALS & METHODS The review employs a systematic approach to gather information on GLP-1RAs. Relevant literature from the currently literature and ongoing clinical trials is thoroughly examined. Detailed scrutiny is applied to understand the mechanism of action, pharmacokinetic properties, and clinical outcomes of these agents. RESULTS The review presents a comprehensive overview of the GLP-1RAs, highlighting their distinct mechanisms of action, pharmacokinetic profiles, and clinical effectiveness in glycemic control and weight management. Safety profiles are also discussed, providing a holistic understanding of these therapeutic agents. DISCUSSION The findings are discussed in the context of advancements in the field of GLP-1RAs. Potential applications beyond diabetes and obesity are explored, shedding light on the broader implications of these agents in managing related conditions. CONCLUSION In conclusion, this review underscores the significance of GLP-1RAs, with a specific focus on semaglutide, in the management of type 2 diabetes, obesity, and beyond. By synthesizing information on their mechanisms, pharmacokinetics, efficacy, and safety, this review provides valuable insights into the potential benefits these agents offer, contributing to the ongoing discourse in the field.
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Deng Y, Li K, Li A, Hu W, Hu W. Advances in the treatment of hepatogenous diabetes: A review. Medicine (Baltimore) 2023; 102:e36068. [PMID: 37986334 PMCID: PMC10659649 DOI: 10.1097/md.0000000000036068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/18/2023] [Accepted: 10/20/2023] [Indexed: 11/22/2023] Open
Abstract
Hepatogenous diabetes (HD) is a glycogen metabolism disorder that arises as a consequence of chronic liver disease. The condition is frequently detected in patients diagnosed with cirrhosis, which is a result of advanced liver disease. The prognosis for patients with HD is generally poor, and they are at a heightened risk for serious complications such as gastrointestinal bleeding, primary peritonitis, and hepatic encephalopathy. Hepatogenous diabetes progression is often associated with cirrhosis progression, which leads to the development of liver cancer and increased patient mortality. Despite the prevalence and severity of HD, no systematic treatment strategy for clinical management of the condition has been proposed by any research or institutions to date. This paper conducts an extensive review of recent advancements in HD treatment in the quest for an effective treatment approach that may improve the overall prognosis of HD.
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Affiliation(s)
- Yanru Deng
- Department of Clinical Nutrition, West China Hospital; Sichuan University, Chengdu, Sichuan Province, China
| | - Keyu Li
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital; Sichuan University, Chengdu, Sichuan Province, China
| | - Ang Li
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital; Sichuan University, Chengdu, Sichuan Province, China
| | - WeiMing Hu
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital; Sichuan University, Chengdu, Sichuan Province, China
| | - Wen Hu
- Department of Clinical Nutrition, West China Hospital; Sichuan University, Chengdu, Sichuan Province, China
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Deng M, Wen Y, Yan J, Fan Y, Wang Z, Zhang R, Ren L, Ba Y, Wang H, Lu Q, Fan H. Comparative effectiveness of multiple different treatment regimens for nonalcoholic fatty liver disease with type 2 diabetes mellitus: a systematic review and Bayesian network meta-analysis of randomised controlled trials. BMC Med 2023; 21:447. [PMID: 37974258 PMCID: PMC10655371 DOI: 10.1186/s12916-023-03129-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 10/25/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely related and mutually contribute to the disease's development. There are many treatment options available to patients. We provide a comprehensive overview of the evidence on the treatment effects of several potential interventions for NAFLD with T2DM. METHODS This systematic review and network meta-analysis included searches of PubMed, Embase, Cochrane Library, and Web of Science from inception to June 30, 2023, for randomised controlled trials of treatment of NAFLD with T2DM. We performed Bayesian network meta-analyses to summarise effect estimates of comparisons between interventions. We applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) frameworks to rate all comparative outcomes' certainty in effect estimates, categorise interventions, and present the findings. This study was registered with PROSPERO, CRD42022342373. RESULTS Four thousand three hundred and sixty-nine records were retrieved from the database and other methods, of which 24 records were eligible for studies enrolling 1589 participants. Eight clinical indicators and 14 interventions were finally in focus. Referring to the lower surface under the cumulative ranking curves (SUCRA) and the league matrix table, exenatide and liraglutide, which are also glucagon-like peptide-1 receptor agonists (GLP-1RAs), showed excellent potential to reduce liver fat content, control glycemia, reduce body weight, and improve liver function and insulin resistance. Exenatide was more effective in reducing glycated haemoglobin (HbA1c) (mean difference (MD) 0.32, 95%CI 0.12 to 0.52), lowering BMI (MD 0.81, 95%CI 0.18 to 1.45), and lowering alanine transaminase (ALT) (MD 10.96, 95%CI 5.27 to 16.66) compared to liraglutide. However, this evidence was assessed as low certainty. Omega-3 was the only intervention that did not have a tendency to lower HbA1c, with standard-treatment (STA-TRE) as reference (MD - 0.17, 95%CI - 0.42 to 0.07). Glimepiride is the only intervention that causes an increase in ALT levels, with standard-treatment (STA-TRE) as reference (MD - 11.72, 95%CI - 17.82 to - 5.57). Based on the available evidence, the treatment effects of pioglitazone, dapagliflozin, and liraglutide have a high degree of confidence. CONCLUSIONS The high confidence mandates the confident application of these findings as guides for clinical practice. Dapagliflozin and pioglitazone are used for glycaemic control in patients with NAFLD combined with T2DM, and liraglutide is used for weight loss therapy in patients with abdominal obesity. The available evidence does not demonstrate the credibility of the effectiveness of other interventions in reducing liver fat content, visceral fat area, ALT, and insulin resistance. Future studies should focus on the clinical application of GLP-1Ras and the long-term prognosis of patients.
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Affiliation(s)
- Manjun Deng
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Xining, 810000, Qinghai, China
| | - Yonghao Wen
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
| | - JingXin Yan
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
- Department of Interventional Therapy, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
| | - Yichen Fan
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
| | - Zhixin Wang
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Xining, 810000, Qinghai, China
| | - Ruixia Zhang
- Department of Endocrinology, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
| | - Li Ren
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Xining, 810000, Qinghai, China
| | - Yinggui Ba
- Department of Nephrology, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
| | - Haijiu Wang
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Xining, 810000, Qinghai, China
| | - Qian Lu
- Department of Hepatopancreatobiliary Surgery, Tsinghua Changgung Hospital, Tsinghua University, Beijing, 102218, China.
| | - Haining Fan
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China.
- Qinghai Research Key Laboratory for Echinococcosis, Xining, 810000, Qinghai, China.
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Bhardwaj M, Gour A, Ahmed A, Dhiman S, Manhas D, Khajuria P, Wazir P, Mukherjee D, Nandi U. Impact of Disease States on the Oral Pharmacokinetics of EIDD-1931 (an Active Form of Molnupiravir) in Rats for Implication in the Dose Adjustment. Mol Pharm 2023; 20:4597-4610. [PMID: 37527414 DOI: 10.1021/acs.molpharmaceut.3c00314] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/03/2023]
Abstract
The pharmacokinetic alteration of an antimicrobial medication leading to sub-therapeutic plasma level can aid in the emergence of resistance, a global threat nowadays. In this context, molnupiravir (prodrug of EIDD-1931) is the most efficacious orally against corona virus disease (COVID-19). In addition to drug-drug interaction, the pharmacokinetics of a drug can significantly vary during any disease state, leading to disease-drug interaction. However, no information is available for such a recently approved drug. Therefore, we aimed to explore the oral pharmacokinetics of EIDD-1931 in seven chemically induced disease states individually compared to the normal state using various rat models. Induction of any disease situation was confirmed by the disease specific study(s) prior to pharmacokinetic investigations. Compared to the normal state, substantially lowered plasma exposure (0.47- and 0.63-fold) with notably enhanced clearance (2.00- and 1.56-fold) of EIDD-1931 was observed in rats of ethanol-induced gastric injury and carbon tetrachloride-induced liver injury states. Conversely, paclitaxel-induced neuropathic pain and cisplatin-induced kidney injury states exhibited opposite outcomes on oral exposure (1.43- and 1.50-fold) and clearance (0.69- and 0.65-fold) of EIDD-1931. Although the highest plasma concentration (2.26-fold) markedly augmented in the doxorubicin-induced cardiac injury state, streptozocin-induced diabetes and lipopolysaccharide-induced lung injury state did not substantially influence the pharmacokinetics of EIDD-1931. Exploring the possible phenomenon behind the reduced or boosted plasma exposure of EIDD-1931, results suggest the need for dose adjustment in respective diseased conditions in order to achieve desired efficacy during oral therapy of EIDD-1931.
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Affiliation(s)
- Mahir Bhardwaj
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Abhishek Gour
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Ajaz Ahmed
- Natural Product and Medicinal Chemistry (NPMC) Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Sumit Dhiman
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Diksha Manhas
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Parul Khajuria
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Priya Wazir
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Debaraj Mukherjee
- Natural Product and Medicinal Chemistry (NPMC) Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Utpal Nandi
- Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
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Scheen AJ. Pharmacokinetic, toxicological, and clinical considerations for the treatment of type 2 diabetes in patients with liver disease: a comprehensive update. Expert Opin Drug Metab Toxicol 2023; 19:543-553. [PMID: 37620287 DOI: 10.1080/17425255.2023.2252333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/22/2023] [Accepted: 08/23/2023] [Indexed: 08/26/2023]
Abstract
INTRODUCTION Type 2 diabetes and liver disease, mainly metabolic-associated fatty liver disease (MAFLD) and more rarely cirrhosis, coexist in many patients. This duality has direct implications for the physician when choosing glucose-lowering agents, with classical concerns but also recent new hopes. AREAS COVERED This updated comprehensive review will consider the pharmacokinetics, the tolerance/safety profile, the benefit/risk balance in cirrhosis, the effects on MAFLD and the risk of hepatocellular carcinoma of old and new glucose-lowering compounds in patients with liver disease, with a special focus on glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. EXPERT OPINION We are currently facing a new paradigm in the management of patients with diabetes and liver disease. From previous reluctance when using antidiabetic agents (except insulin) in diabetic patients with hepatic impairment because of safety concerns, the commercialization of novel glucose-lowering agents has changed the scene. These agents, which have a good safety profile, are associated with weight loss and pleiotropic effects. They have proven their efficacy in improving MAFLD. However, more specific studies are still needed to prove their efficacy in preventing the progression to fibrosis/cirrhosis and confirm this new opportunity for the management of patients with diabetes and liver disease.
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Affiliation(s)
- André J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), Liège University, Liège, Belgium
- Division of Diabetes, Nutrition and Metabolic Disorders, CHU Liège, Liège, Belgium
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Licata A, Russo GT, Giandalia A, Cammilleri M, Asero C, Cacciola I. Impact of Sex and Gender on Clinical Management of Patients with Advanced Chronic Liver Disease and Type 2 Diabetes. J Pers Med 2023; 13:jpm13030558. [PMID: 36983739 PMCID: PMC10051396 DOI: 10.3390/jpm13030558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/22/2023] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
Gender differences in the epidemiology, pathophysiological mechanisms and clinical features in chronic liver diseases that may be associated with type 2 diabetes (T2D) have been increasingly reported in recent years. This sexual dimorphism is due to a complex interaction between sex- and gender-related factors, including biological, hormonal, psychological and socio-cultural variables. However, the impact of sex and gender on the management of T2D subjects with liver disease is still unclear. In this regard, sex-related differences deserve careful consideration in pharmacology, aimed at improving drug safety and optimising medical therapy, both in men and women with T2D; moreover, low adherence to and persistence of long-term drug treatment is more common among women. A better understanding of sex- and gender-related differences in this field would provide an opportunity for a tailored diagnostic and therapeutic approach to the management of T2D subjects with chronic liver disease. In this narrative review, we summarized available data on sex- and gender-related differences in chronic liver disease, including metabolic, autoimmune, alcoholic and virus-related forms and their potential evolution towards cirrhosis and/or hepatocarcinoma in T2D subjects, to support their appropriate and personalized clinical management.
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Affiliation(s)
- Anna Licata
- Internal Medicine & Hepatology Unit, University Hospital of Palermo, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Giuseppina T Russo
- Internal Medicine and Diabetology Unit, University of Messina, 98125 Messina, Italy
| | - Annalisa Giandalia
- Internal Medicine and Hepatology Unit, University Hospital of Messina, 98124 Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
| | - Marcella Cammilleri
- Internal Medicine & Hepatology Unit, University Hospital of Palermo, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Clelia Asero
- Internal Medicine and Hepatology Unit, University Hospital of Messina, 98124 Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
| | - Irene Cacciola
- Internal Medicine and Hepatology Unit, University Hospital of Messina, 98124 Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, 98124 Messina, Italy
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Alqahtan SA, Brown RS. Management and Risks Before, During, and After Liver Transplant in Individuals With Obesity. Gastroenterol Hepatol (N Y) 2023; 19:20-29. [PMID: 36865816 PMCID: PMC9972654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023]
Abstract
Obesity has become a global epidemic, adding to the burden of chronic diseases and disabilities. Metabolic syndrome, especially obesity, is a significant risk factor for nonalcoholic fatty liver disease, which is the most common indication for liver transplant (LT). The prevalence of obesity among the LT population is growing. Obesity increases the necessity of LT by playing a role in the development of nonalcoholic fatty liver disease, decompensated cirrhosis, and hepatocellular carcinoma, and it can also coexist with other diseases requiring LT. Therefore, LT teams must identify key aspects required to manage this high-risk population, but there are currently no defined recommendations for managing obesity in LT candidates. Although body mass index is often used to assess the weight of patients and classify them as overweight or obese, this measure may be inaccurate to use in patients with decompensated cirrhosis, as fluid overload or ascites can significantly add to the weight of patients. Diet and exercise remain the cornerstone of obesity management. Supervised weight loss before LT, without worsening frailty and sarcopenia, may be beneficial in reducing surgical risks and improving long-term LT outcomes. Bariatric surgery is another effective treatment for obesity, with sleeve gastrectomy currently conferring the best outcomes in LT recipients. However, evidence supporting the timing of bariatric surgery is lacking. Long-term patient and graft survival data in individuals with obesity following LT are scarce. Class 3 obesity (body mass index ≥40) further complicates the treatment of this patient population. This article discusses the impact of obesity on the outcome of LT.
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Affiliation(s)
- Saleh A. Alqahtan
- 1Liver Transplant Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia,2Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland
| | - Robert S. Brown
- 3Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, New York
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Arvanitakis K, Koufakis T, Kotsa K, Germanidis G. How Far beyond Diabetes Can the Benefits of Glucagon-like Peptide-1 Receptor Agonists Go? A Review of the Evidence on Their Effects on Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14194651. [PMID: 36230573 PMCID: PMC9562923 DOI: 10.3390/cancers14194651] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 09/20/2022] [Accepted: 09/22/2022] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is characterized by poor survival rate and quality of life, while available treatments remain generally limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) originally emerged as drugs for the management of diabetes, but have also been shown to alleviate cardiorenal risk. Furthermore, they have demonstrated a wide range of extraglycemic effects that led to their evaluation as potential therapies for a variety of diseases beyond diabetes, such as obesity, neurogenerative disorders and nonalcoholic fatty liver disease. Given the presence of the GLP-1 receptor in hepatocytes, animal data suggest that GLP-1 RAs could regulate molecular pathways that are deeply involved in the genesis and progression of HCC, including inflammatory responses, tumor cell proliferation and oxidative stress, through direct and indirect effects on liver cells. However, future studies must assess several aspects of the benefit-to-risk ratio of the use of GLP-1 RAs in patients with HCC, including co-administration with approved systemic therapies, the incidence of gastrointestinal side effects in a high-risk population, and weight loss management in individuals with poor nutritional status and high rates of cancer cachexia. In this narrative review, we discuss the potential role of GLP-1 analogs in the treatment of HCC, focusing on the molecular mechanisms that could justify a possible benefit, but also referring to the potential clinical implications and areas for future research.
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Affiliation(s)
- Konstantinos Arvanitakis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
- Basic and Translational Research Unit (BTRU) of Special Unit for Biomedical Research and Education (SUBRE), School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, AHEPA University Hospital, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, AHEPA University Hospital, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Georgios Germanidis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
- Basic and Translational Research Unit (BTRU) of Special Unit for Biomedical Research and Education (SUBRE), School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
- Correspondence: ; Tel.: +30-231-330-3156; Fax: +30-231-099-4638
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Roeb E, Canbay A, Bantel H, Bojunga J, de Laffolie J, Demir M, Denzer UW, Geier A, Hofmann WP, Hudert C, Karlas T, Krawczyk M, Longerich T, Luedde T, Roden M, Schattenberg J, Sterneck M, Tannapfel A, Lorenz P, Tacke F. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:1346-1421. [PMID: 36100202 DOI: 10.1055/a-1880-2283] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- E Roeb
- Gastroenterologie, Medizinische Klinik II, Universitätsklinikum Gießen und Marburg, Gießen, Deutschland
| | - A Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - H Bantel
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - J Bojunga
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin., Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - J de Laffolie
- Allgemeinpädiatrie und Neonatologie, Zentrum für Kinderheilkunde und Jugendmedizin, Universitätsklinikum Gießen und Marburg, Gießen, Deutschland
| | - M Demir
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum und Campus Charité Mitte, Berlin, Deutschland
| | - U W Denzer
- Klinik für Gastroenterologie und Endokrinologie, Universitätsklinikum Gießen und Marburg, Marburg, Deutschland
| | - A Geier
- Medizinische Klinik und Poliklinik II, Schwerpunkt Hepatologie, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - W P Hofmann
- Gastroenterologie am Bayerischen Platz - Medizinisches Versorgungszentrum, Berlin, Deutschland
| | - C Hudert
- Klinik für Pädiatrie m. S. Gastroenterologie, Nephrologie und Stoffwechselmedizin, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - T Karlas
- Klinik und Poliklinik für Onkologie, Gastroenterologie, Hepatologie, Pneumologie und Infektiologie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - M Krawczyk
- Klinik für Innere Medizin II, Gastroent., Hepat., Endokrin., Diabet., Ern.med., Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - T Longerich
- Pathologisches Institut, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - T Luedde
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland
| | - M Roden
- Klinik für Endokrinologie und Diabetologie, Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland
| | - J Schattenberg
- I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Mainz, Deutschland
| | - M Sterneck
- Klinik für Hepatobiliäre Chirurgie und Transplantationschirurgie, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - A Tannapfel
- Institut für Pathologie, Ruhr-Universität Bochum, Bochum, Deutschland
| | - P Lorenz
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin, Deutschland
| | - F Tacke
- Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum und Campus Charité Mitte, Berlin, Deutschland
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12
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Population Pharmacokinetics of Cotadutide in Subjects with Type 2 Diabetes. Clin Pharmacokinet 2022; 61:833-845. [PMID: 35235191 DOI: 10.1007/s40262-021-01094-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2021] [Indexed: 11/03/2022]
Abstract
BACKGROUND AND OBJECTIVES Cotadutide is a balanced dual glucagon-like peptide-1/glucagon receptor agonist under development for the treatment of nonalcoholic steatohepatitis and chronic kidney disease with type 2 diabetes. The objectives of the analysis were to characterize the population pharmacokinetics of cotadutide following daily subcutaneous injection in subjects with type 2 diabetes and to evaluate the effect of demographic and clinical variables of interest on cotadutide pharmacokinetics. METHODS This study analyzed 8834 plasma concentrations of cotadutide from 759 subjects with type 2 diabetes who received daily subcutaneous doses from 20 to 600 μg from six clinical studies. The impact of covariates on cotadutide pharmacokinetics was quantified, and body weight effect on cotadutide exposure was further evaluated using a simulation approach. The model performance was evaluated through prediction-corrected visual predictive checks. RESULTS A one-compartment model with first-order absorption and elimination described cotadutide pharmacokinetic data well. The mean values for cotadutide apparent clearance, apparent distribution volume, absorption rate constant, and half-life were 1.04 L/h (interindividual variability [IIV]: 26.5%), 18.7 L (IIV: 28.7%), 0.343 h-1 (IIV: 38.6%), and 12.9 h, respectively. Higher body weight, lower albumin, and higher alanine aminotransferase were associated with an increase in cotadutide clearance, while an increase in anti-drug antibody titers was associated with a decrease in cotadutide clearance. These statistically significant effects were not considered clinically significant and did not warrant dose adjustment. Effects of other tested baseline covariates (age, sex, body mass index, hemoglobin A1c, renal function, duration of diabetes) were not found to statistically significantly affect cotadutide pharmacokinetics. CONCLUSIONS Cotadutide pharmacokinetics was adequately described by a one-compartment linear model with first-order absorption and elimination. Body weight-based dosing is not necessary for cotadutide based on the simulation using the final population pharmacokinetic modeling. This model will be used to evaluate exposure-response relationships for efficacy and safety in different indications that are being studied for cotadutide.
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13
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Brodosi L, Petta S, Petroni ML, Marchesini G, Morelli MC. Management of Diabetes in Candidates for Liver Transplantation and in Transplant Recipients. Transplantation 2022; 106:462-478. [PMID: 34172646 PMCID: PMC9904447 DOI: 10.1097/tp.0000000000003867] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 11/25/2022]
Abstract
Diabetes is common in patients waitlisted for liver transplantation because of end-stage liver disease or hepatocellular cancer as well as in posttransplant phase (posttransplantation diabetes mellitus). In both conditions, the presence of diabetes severely affects disease burden and long-term clinical outcomes; careful monitoring and appropriate treatment are pivotal to reduce cardiovascular events and graft and recipients' death. We thoroughly reviewed the epidemiology of diabetes in the transplant setting and the different therapeutic options, from lifestyle intervention to antidiabetic drug use-including the most recent drug classes available-and to the inclusion of bariatric surgery in the treatment cascade. In waitlisted patients, the old paradigm that insulin should be the treatment of choice in the presence of severe liver dysfunction is no longer valid; novel antidiabetic agents may provide adequate glucose control without the risk of hypoglycemia, also offering cardiovascular protection. The same evidence applies to the posttransplant phase, where oral or injectable noninsulin agents should be considered to treat patients to target, limiting the impact of disease on daily living, without interaction with immunosuppressive regimens. The increasing prevalence of liver disease of metabolic origin (nonalcoholic fatty liver) among liver transplant candidates, also having a higher risk of noncirrhotic hepatocellular cancer, is likely to accelerate the acceptance of new drugs and invasive procedures, as suggested by international guidelines. Intensive lifestyle intervention programs remain however mandatory, both before and after transplantation. Achievement of adequate control is mandatory to increase candidacy, to prevent delisting, and to improve long-term outcomes.
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Affiliation(s)
- Lucia Brodosi
- IRCCS – Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, Alma Mater University, Bologna, Italy
| | - Salvatore Petta
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Maria L. Petroni
- IRCCS – Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, Alma Mater University, Bologna, Italy
| | - Giulio Marchesini
- IRCCS – Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, Alma Mater University, Bologna, Italy
| | - Maria C. Morelli
- IRCCS – Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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14
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Puri P, Kotwal N. An Approach to the Management of Diabetes Mellitus in Cirrhosis: A Primer for the Hepatologist. J Clin Exp Hepatol 2022; 12:560-574. [PMID: 35535116 PMCID: PMC9077234 DOI: 10.1016/j.jceh.2021.09.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 09/07/2021] [Indexed: 12/12/2022] Open
Abstract
The management of diabetes in cirrhosis and liver transplantation can be challenging. There is difficulty in diagnosis and monitoring of diabetes as fasting blood sugar values are low and glycosylated hemoglobin may not be a reliable marker. The challenges in the management of diabetes in cirrhosis include the likelihood of cognitive impairment, risk of hypoglycemia, altered drug metabolism, frequent renal dysfunction, risk of lactic acidosis, and associated malnutrition and sarcopenia. Moreover, calorie restriction and an attempt to lose weight in obese diabetics may be associated with a worsening of sarcopenia. Many commonly used antidiabetic drugs may be unsafe or be associated with a high risk of hypoglycemia in cirrhotics. Post-transplant diabetes is common and may be contributed by immunosuppressive medication. There is inadequate clinical data on the use of antidiabetic drugs in cirrhosis, and the management of diabetes in cirrhosis is hampered by the lack of guidelines focusing on this issue. The current review aims at addressing the practical management of diabetes by a hepatologist.
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Key Words
- ADA, American Diabetes Association
- AGI, Alfa Glucosidase inhibitors
- BMI, Body mass index
- CLD, Chronic liver disease
- CYP-450, Cytochrome P-450
- Dipeptidyl-peptidase 4, DPP-4
- GLP-1, Glucagon-like peptide-1
- HCC, Hepatocellular carcinoma
- HCV, Hepatitis C virus
- HbA1c, Hemoglobin A1c
- IGF, Insulin-like growth factor
- MALA, Metformin-associated lactic acidosis
- NASH, Nonalcoholic steatohepatitis
- NPL, Neutral protamine lispro
- OGTT, Oral glucose tolerance test
- SMBG, Self-monitoring of blood glucose
- Sodium-glucose cotransporter 2, SGLT2
- VEGF, Vascular endothelial growth factor
- antidiabetic agents
- antihyperglycemic drugs
- chronic liver disease
- cirrhosis
- diabetes mellitus
- eGFR, estimated glomerular filtration rates
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Affiliation(s)
- Pankaj Puri
- Fortis Escorts Liver and Digestive Diseases Institute, New Delhi, 110025, India
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15
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Mahmood I, Pettinato M. Impact of Intrinsic and Extrinsic Factors on the Pharmacokinetics of Peptides: When Is the Assessment of Certain Factors Warranted? Antibodies (Basel) 2021; 11:antib11010001. [PMID: 35076485 PMCID: PMC8788552 DOI: 10.3390/antib11010001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 11/01/2021] [Accepted: 12/19/2021] [Indexed: 12/29/2022] Open
Abstract
Peptides are short chains of 2 to 50 amino acids (molecular weight of less than 10 kDa) linked together by peptide bonds. As therapeutic agents, peptides are of interest because the body naturally produces many different peptides. Short-chain peptides have many advantages as compared with long-chain peptides (e.g., low toxicity). The first peptide corticotropin was approved in 1952 for multiple inflammatory diseases and West syndrome. Since then, more than 60 peptides have been approved by the FDA. Pharmacokinetics (PK) is widely used in modern-day drug development for designing a safe and efficacious dose to treat a wide variety of diseases. There are, however, several factors termed as “intrinsic” or “extrinsic” which can influence the PK of a drug, and as a result, one has to adjust the dose in a patient population. These intrinsic and extrinsic factors can be described as age, gender, disease states such as renal and hepatic impairment, drug–drug interaction, food, smoking, and alcohol consumption. It is well known that these intrinsic and extrinsic factors can have a substantial impact on the PK of small molecules, but for macromolecules, the impact of these factors is not well established. This review summarizes the impact of intrinsic and extrinsic factors on the PK of peptides.
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16
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Chen J, Gu J, Shah B, Stringer R, Torrao LRDS, Hackling M, Nidamarthy PK, Prince WT, Woessner R. Pharmacokinetics of Tropifexor, a Potent Farnesoid X Receptor Agonist, in Participants With Varying Degrees of Hepatic Impairment. J Clin Pharmacol 2021; 62:520-531. [PMID: 34738233 DOI: 10.1002/jcph.1996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 10/28/2021] [Indexed: 11/07/2022]
Abstract
Tropifexor, a non-bile acid farnesoid X receptor (FXR) agonist, has dose-proportional pharmacokinetics (PK) and no obvious major enterohepatic circulation. This open-label study investigated the effect of hepatic impairment (HI), as determined by Child-Pugh grade, on tropifexor's PK, safety, and tolerability following a 200-μg dose in the fasted state. Blood samples were collected through 168 hours after dosing for quantification and plasma protein-binding determination. Total tropifexor exposure was comparable across participants with HI vs those with normal hepatic function. Tropifexor was highly protein bound (>99%) in human plasma across participants of all groups. The average unbound fractions (percent free) were 0.14% in participants with normal hepatic function and mild HI, which increased to 0.17% and 0.24% in participants with moderate and severe HI, respectively. Similar unbound drug exposure was noted in participants with mild HI and normal hepatic function. Participants with moderate HI (N = 8) had a 1.6-fold increase in unbound exposure (area under the plasma concentration-time curve from time 0 to infinity [AUCinf, u ]) and a 1.3-fold increase in maximal exposure (Cmax,u ) vs those with normal hepatic function (geometric mean ratio: AUCinf, u = 1.64 [90% CI, 1.25-2.16]; Cmax,u = 1.30 [0.96-1.76]). Participants with severe HI (N = 8) had a 1.6-fold increase in AUCinf, u (1.61 [1.04-2.49]) and comparable Cmax,u (1.02 [0.60-1.72]) compared to participants with normal hepatic function. Tropifexor was well tolerated. The relative insensitivity of tropifexor to HI offers the potential to treat patients with severe liver disease without dose adjustment. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Jin Chen
- Novartis Institutes for Biomedical Research, East Hanover, New Jersey, USA
| | - Jessie Gu
- Novartis Institute for Biomedical Research, Cambridge, Massachusetts, USA
| | - Bharti Shah
- Novartis Institutes for Biomedical Research, East Hanover, New Jersey, USA
| | - Rowan Stringer
- Novartis Institute for Biomedical Research, Basel, Switzerland
| | | | - Melissa Hackling
- Novartis Institutes for Biomedical Research, East Hanover, New Jersey, USA
| | | | - William T Prince
- Novartis Institute for Biomedical Research, Cambridge, Massachusetts, USA
| | - Ralph Woessner
- Novartis Institute for Biomedical Research, Basel, Switzerland
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17
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Management of diabetes mellitus in patients with cirrhosis: An overview and joint statement. DIABETES & METABOLISM 2021; 47:101272. [PMID: 34363981 DOI: 10.1016/j.diabet.2021.101272] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/25/2021] [Accepted: 07/12/2021] [Indexed: 12/18/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a frequent comorbidity in patients with cirrhosis that is projected to rise in prevalence due to the worldwide burden of obesity, insulin-resistance and non-alcoholic fatty liver disease. The management of T2DM in patients with cirrhosis is complex given the requirement for accurate adaptation according to the level of liver function impairment, with lack of summary of the little evidence available in the literature. Here, we summarise the data available with respect to the epidemiology and the impact of T2DM in patients with cirrhosis, as well as those on the management of T2DM in these patients. We provide guidance for the diagnosis of T2DM and the monitoring of glycaemic control in patients with cirrhosis, and for the management of nutrition and pharmacological treatments in relation to the level of liver dysfunction.
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18
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Brown SA, Izzy M, Watt KD. Pharmacotherapy for Weight Loss in Cirrhosis and Liver Transplantation: Translating the Data and Underused Potential. Hepatology 2021; 73:2051-2062. [PMID: 33047343 DOI: 10.1002/hep.31595] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 08/30/2020] [Accepted: 09/24/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Thirty percent of patients with cirrhosis are obese and the prevalence of obesity increases after transplant to >40% post-transplant. There are currently four weight loss medications approved by the FDA for treatment of obesity (orlistat, phentermine-topiramate, naltrexone-bupropion, and liraglutide). The aim of this review was to investigate the data on the use of these weight loss medications and alternative medicines in patients with cirrhosis and in liver transplant recipients (LTRs). APPROACH AND RESULTS While there is paucity of data for these medications in patients with cirrhosis and LTRs, Liraglutide appears to be generally safe in view of its pharmacokinetic properties. Phentermine-topiramate seems to have the highest weight loss potential but special consideration should be given to neuropsychiatric disorders, cardiovascular comorbidities, and drug interactions. There are emerging data on use of alternative medicines for weight loss but more data are needed. CONCLUSIONS The use of weight loss medications is feasible in this patient population but the decision of which medication to prescribe should be individualized based on the degree of renal and hepatic impairment, other co-morbidities, and concomitant medications.
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Affiliation(s)
- Sara A Brown
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University, Nashville, TN, USA
| | - Manhal Izzy
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University, Nashville, TN, USA
| | - Kymberly D Watt
- Division of Gastroenterology and Hepatology, The Mayo Clinic, Rochester, MN, USA
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19
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Lin CH, Shao L, Zhang YM, Tu YJ, Zhang Y, Tomlinson B, Chan P, Liu Z. An evaluation of liraglutide including its efficacy and safety for the treatment of obesity. Expert Opin Pharmacother 2019; 21:275-285. [PMID: 31790314 DOI: 10.1080/14656566.2019.1695779] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: The prevalence of obesity is increasing worldwide and associated conditions, particularly type 2 diabetes mellitus (T2DM), also show increasing prevalence. Lifestyle intervention should be the first line of management for obesity but additional pharmacotherapy is often required and bariatric surgery is appropriate in more severe cases. Drugs acting as glucagon-like peptide-1 receptor agonists (GLP-1RAs) developed for the management of T2DM reduce body weight and liraglutide is the first GLP-1RA to be approved for the treatment of obesity in patients with and without T2DM.Areas covered: In this review of relevant published material, the authors summarize the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of liraglutide for the treatment of obesity.Expert opinion: Liraglutide effectively reduces body weight and body fat through mechanisms involving reduced appetite and lowered energy intake, independent of its glucose-lowering effects. Like most of the other medications currently available for obesity, liraglutide has some common adverse effects, although generally not serious ones. Liraglutide has additional benefits in reducing cardiovascular events in patients with T2DM but the cost and the need for daily injections may limit its use in obesity. Newer GLP-1RAs, such as semaglutide, or other drugs in development for obesity may have advantages over liraglutide.
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Affiliation(s)
- Chen-Hsiu Lin
- Division of Cardiology, Department of Internal Medicine, Taipei Medical University, Taipei, Taiwan
| | - Li Shao
- The VIP Department, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yu-Mei Zhang
- The VIP Department, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yu-Ju Tu
- The VIP Department, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuzhen Zhang
- Research Center for Translational Medicine, Shanghai East Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
| | - Brian Tomlinson
- Research Center for Translational Medicine, Shanghai East Hospital Affiliated to Tongji University School of Medicine, Shanghai, China.,Faculty of Medicine, Macau University of Science and Technology, Taipa, Macau
| | - Paul Chan
- Division of Cardiology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan
| | - Zhongmin Liu
- Department of Cardiac Surgery, Shanghai East Hospital, Tongji University, Shanghai, China
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20
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Kalra S, Das AK, Sahay RK, Baruah MP, Tiwaskar M, Das S, Chatterjee S, Saboo B, Bantwal G, Bhattacharya S, Priya G, Chawla M, Brar K, Raza SA, Aamir AH, Shrestha D, Somasundaram N, Katulanda P, Afsana F, Selim S, Naseri MW, Latheef A, Sumanatilleke M. Consensus Recommendations on GLP-1 RA Use in the Management of Type 2 Diabetes Mellitus: South Asian Task Force. Diabetes Ther 2019; 10:1645-1717. [PMID: 31359367 PMCID: PMC6778554 DOI: 10.1007/s13300-019-0669-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Indexed: 12/17/2022] Open
Abstract
The advent of incretin mimetics such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has enriched the armamentarium for diabetes management owing to their glycaemic as well as extra-glycaemic benefits. The approval status and availability of this class of drugs vary widely across the globe. Being a relatively newer class of drug with numerous benefits, several national and international guidelines are working towards addressing clinical questions pertaining to the optimal use of GLP-1 RAs for the management of diabetes. Although the newer class of drugs are associated with significant benefits such as patient-centric approach, these drugs demand the providers to be vigilant and knowledgeable about the medication. The South Asian population is at higher risk of type 2 diabetes mellitus (T2DM) because of their genetic predisposition and lifestyle changes. Hence, prevention and management of T2DM and its associated complications in this population are of paramount importance. The current report aims to present an overview of current knowledge on GLP-1 RAs based on pragmatic review of the available clinical evidence. In addition, this report is a consensus of expert endocrinologists representing South Asian countries including India, Pakistan, Bangladesh, Nepal, Sri Lanka, Afghanistan and the Maldives on essential recommendations related to the use of GLP-1 RAs in a real-world scenario.
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Affiliation(s)
| | - Ashok Kumar Das
- Pondicherry Institute of Medical Sciences, Pondicherry, India
| | | | | | | | - Sambit Das
- Hi Tech Medical College and Hospital, Bhubaneshwar, India
| | | | | | | | | | | | | | | | - Syed Abbas Raza
- Shaukat Khanum Memorial Cancer Hospital and Research Centre and National Defence Hospital, Lahore, Pakistan
| | | | | | | | | | | | - Shahjada Selim
- Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | | | - Ali Latheef
- Department of Medicine, Indra Gandhi Hospital, Male, Maldives
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21
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Papazafiropoulou A, Melidonis A. Antidiabetic agents in patients with hepatic impairment. World J Meta-Anal 2019; 7:380-388. [DOI: 10.13105/wjma.v7.i8.380] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 08/07/2019] [Accepted: 08/20/2019] [Indexed: 02/06/2023] Open
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22
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Knudsen LB. Inventing Liraglutide, a Glucagon-Like Peptide-1 Analogue, for the Treatment of Diabetes and Obesity. ACS Pharmacol Transl Sci 2019; 2:468-484. [PMID: 32259078 DOI: 10.1021/acsptsci.9b00048] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Indexed: 01/08/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) has been in focus since the early 1980s as a long looked for incretin hormone, released from the gastrointestinal tract and with an important effect on glucose-dependent insulin secretion, providing efficient glucose lowering, with little risk for hypoglycemia. The enzyme dipeptidyl peptidase-4 (DPP-4) degrades GLP-1 very fast, and the remaining metabolite is cleared rapidly by the kidneys. Liraglutide is a fatty acid acylated analogue of GLP-1 that provides efficacy for 24 h/day. The mechanism of action for liraglutide is reviewed in detail with focus on pancreatic efficacy and safety, thyroid safety, and weight loss mechanism. Evolving science hypothesizes that GLP-1 has important effects on atherosclerosis, relevant for the cardiovascular benefit seen in the treatment of diabetes and obesity. Also, GLP-1 may be relevant in neurodegenerative diseases.
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Affiliation(s)
- Lotte Bjerre Knudsen
- Global Drug Discovery, Novo Nordisk, Novo Nordisk Park, DK-2760 Maaloev, Denmark
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23
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Determination of the Plasma Protein Binding of Liraglutide Using the EScalate Equilibrium Shift Assay. J Pharm Sci 2019; 108:1309-1314. [DOI: 10.1016/j.xphs.2018.10.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 10/10/2018] [Accepted: 10/10/2018] [Indexed: 11/22/2022]
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Howell R, Wright AM, Clements JN. Clinical potential of liraglutide in cardiovascular risk reduction in patients with type 2 diabetes: evidence to date. Diabetes Metab Syndr Obes 2019; 12:505-512. [PMID: 31118715 PMCID: PMC6475096 DOI: 10.2147/dmso.s174568] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Metformin is the first-line therapy for the management of type 2 diabetes. After 3 months of metformin, add-on therapy can be considered if an individual's glycemic control has not been achieved for hemoglobin A1c, fasting blood glucose levels, and postprandial blood glucose levels. Liraglutide is a potential second-line option for the management of type 2 diabetes mellitus, particularly for those who are or may be at a high risk of cardiovascular disease. It can also be used an add-on therapy for those individuals with established cardiovascular disease. Liraglutide has additional benefits, such as no to minimal risk of hypoglycemia and promotion of weight loss through its mechanism of action. This particular article summarizes evidence on cardiovascular biomarkers and surrogate endpoints, along with macrovascular events, with liraglutide therapy. Overall, liraglutide has extensive cardiovascular evidence based on which it could be used as a desirable agent for glycemic control while lowering the risk of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization from heart failure.
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Affiliation(s)
- Rebecca Howell
- Presbyterian College School of Pharmacy, Clinton, SC 29325, USA
| | | | - Jennifer N Clements
- Department of Pharmacy Practice, Presbyterian College School of Pharmacy, Clinton, SC 29325, USA,
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25
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Knudsen LB, Lau J. The Discovery and Development of Liraglutide and Semaglutide. Front Endocrinol (Lausanne) 2019; 10:155. [PMID: 31031702 PMCID: PMC6474072 DOI: 10.3389/fendo.2019.00155] [Citation(s) in RCA: 506] [Impact Index Per Article: 84.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 02/21/2019] [Indexed: 12/12/2022] Open
Abstract
The discovery of glucagon-like peptide-1 (GLP-1), an incretin hormone with important effects on glycemic control and body weight regulation, led to efforts to extend its half-life and make it therapeutically effective in people with type 2 diabetes (T2D). The development of short- and then long-acting GLP-1 receptor agonists (GLP-1RAs) followed. Our article charts the discovery and development of the long-acting GLP-1 analogs liraglutide and, subsequently, semaglutide. We examine the chemistry employed in designing liraglutide and semaglutide, the human and non-human studies used to investigate their cellular targets and pharmacological effects, and ongoing investigations into new applications and formulations of these drugs. Reversible binding to albumin was used for the systemic protraction of liraglutide and semaglutide, with optimal fatty acid and linker combinations identified to maximize albumin binding while maintaining GLP-1 receptor (GLP-1R) potency. GLP-1RAs mediate their effects via this receptor, which is expressed in the pancreas, gastrointestinal tract, heart, lungs, kidneys, and brain. GLP-1Rs in the pancreas and brain have been shown to account for the respective improvements in glycemic control and body weight that are evident with liraglutide and semaglutide. Both liraglutide and semaglutide also positively affect cardiovascular (CV) outcomes in individuals with T2D, although the precise mechanism is still being explored. Significant weight loss, through an effect to reduce energy intake, led to the approval of liraglutide (3.0 mg) for the treatment of obesity, an indication currently under investigation with semaglutide. Other ongoing investigations with semaglutide include the treatment of non-alcoholic fatty liver disease (NASH) and its use in an oral formulation for the treatment of T2D. In summary, rational design has led to the development of two long-acting GLP-1 analogs, liraglutide and semaglutide, that have made a vast contribution to the management of T2D in terms of improvements in glycemic control, body weight, blood pressure, lipids, beta-cell function, and CV outcomes. Furthermore, the development of an oral formulation for semaglutide may provide individuals with additional benefits in relation to treatment adherence. In addition to T2D, liraglutide is used in the treatment of obesity, while semaglutide is currently under investigation for use in obesity and NASH.
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Affiliation(s)
- Lotte Bjerre Knudsen
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
- *Correspondence: Lotte Bjerre Knudsen
| | - Jesper Lau
- Global Research Technology, Novo Nordisk A/S, Måløv, Denmark
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Menacho-Melgar R, Decker JS, Hennigan JN, Lynch MD. A review of lipidation in the development of advanced protein and peptide therapeutics. J Control Release 2018; 295:1-12. [PMID: 30579981 DOI: 10.1016/j.jconrel.2018.12.032] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 12/16/2018] [Accepted: 12/18/2018] [Indexed: 12/22/2022]
Abstract
The use of biologics (peptide and protein based drugs) has increased significantly over the past few decades. However, their development has been limited by their short half-life, immunogenicity and low membrane permeability, restricting most therapies to extracellular targets and administration by injection. Lipidation is a clinically-proven post-translational modification that has shown great promise to address these issues: improving half-life, reducing immunogenicity and enabling intracellular uptake and delivery across epithelia. Despite its great potential, lipidation remains an underutilized strategy in the clinical translation of lead biologics. We review how lipidation can overcome common challenges in biologics development as well as highlight gaps in our understanding of the effect of lipidation on therapeutic efficacy, where increased research and development efforts may lead to next-generation drugs.
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Affiliation(s)
| | - John S Decker
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | | | - Michael D Lynch
- Department of Biomedical Engineering, Duke University, Durham, NC, USA.
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Morcos PN, Cleary Y, Sturm-Pellanda C, Guerini E, Abt M, Donzelli M, Vazvaei F, Balas B, Parrott N, Yu L. Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib. J Clin Pharmacol 2018; 58:1618-1628. [PMID: 30052269 PMCID: PMC6282775 DOI: 10.1002/jcph.1286] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 06/22/2018] [Indexed: 12/15/2022]
Abstract
Alectinib is approved and recommended as the preferred first‐line treatment for patients with anaplastic lymphoma kinase (ALK)‐positive non–small cell lung cancer. The effect of hepatic impairment on the pharmacokinetics (PK) of alectinib was assessed with physiologically based PK modeling prospectively and in a clinical study. An open‐label study (NCT02621047) investigated a single 300‐mg dose of alectinib in moderate (n = 8) and severe (n = 8) hepatic impairment (Child‐Pugh B/C), and healthy subjects (n = 12) matched for age, sex, and body weight. Physiologically based PK modeling was conducted prospectively to inform the clinical study design and support the use of a lower dose and extended PK sampling in the study. PK parameters were calculated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Unbound concentrations were assessed at 6 and 12 hours postdose. Administration of alectinib to subjects with hepatic impairment increased the area under the plasma concentration–time curve from time 0 to infinity of the combined exposure of alectinib and M4 to 136% (90% confidence interval [CI], 94.7‐196) and 176% (90%CI 98.4‐315), for moderate and severe hepatic impairment, respectively, relative to matched healthy subjects. Unbound concentrations for alectinib and M4 did not appear substantially different between hepatic‐impaired and healthy subjects. Moderate hepatic impairment had only a modest, not clinically significant effect on alectinib exposure, while the higher exposure observed in severe hepatic impairment supports a dose adjustment in this population.
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Affiliation(s)
| | | | | | | | - Markus Abt
- F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | | | | | | | | | - Li Yu
- Roche Innovation Center, New York City, NY, USA
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Bækdal TA, Thomsen M, Kupčová V, Hansen CW, Anderson TW. Pharmacokinetics, Safety, and Tolerability of Oral Semaglutide in Subjects With Hepatic Impairment. J Clin Pharmacol 2018; 58:1314-1323. [PMID: 29693715 PMCID: PMC6175428 DOI: 10.1002/jcph.1131] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 03/08/2018] [Indexed: 01/14/2023]
Abstract
Semaglutide is a human glucagon‐like peptide‐1 analog that has been co‐formulated with the absorption enhancer, sodium N‐(8‐[2‐hydroxybenzoyl] amino) caprylate, for oral administration. This trial (NCT02016911) investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of oral semaglutide. Subjects were classified into groups: normal hepatic function (n = 24), and mild (n = 12), moderate (n = 12), or severe (n = 8) hepatic impairment according to Child‐Pugh criteria, and received once‐daily oral semaglutide (5 mg for 5 days followed by 10 mg for 5 days). Semaglutide plasma concentrations were measured during dosing and for up to 21 days post‐last dose. Area under the semaglutide plasma concentration–time curve from 0–24 hours after the 10th dose (primary end point) and maximum semaglutide concentration after the 10th dose appeared similar across hepatic function groups. Similarly, there was no apparent effect of hepatic impairment on time to maximum semaglutide concentration (median range 1.0–1.5 hours) or half‐life (geometric mean range 142–156 hours). No safety concerns were identified in subjects with hepatic impairment receiving semaglutide. Reported adverse events were in line with those observed for other glucagon‐like peptide‐1 receptor agonists. There was no apparent effect of hepatic impairment on the pharmacokinetics, safety, and tolerability of oral semaglutide. The results of this trial suggest that dose adjustment of oral semaglutide is not warranted in subjects with hepatic impairment.
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Affiliation(s)
| | | | - Viera Kupčová
- 3rd Department of Internal MedicineDérer's HospitalBratislavaSlovakia
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Jensen L, Kupcova V, Arold G, Pettersson J, Hjerpsted JB. Pharmacokinetics and tolerability of semaglutide in people with hepatic impairment. Diabetes Obes Metab 2018; 20:998-1005. [PMID: 29205786 PMCID: PMC5873441 DOI: 10.1111/dom.13186] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 11/13/2017] [Accepted: 11/30/2017] [Indexed: 12/25/2022]
Abstract
AIMS To investigate whether the pharmacokinetic characteristics of semaglutide were altered in people with hepatic impairment, assessed using Child-Pugh criteria, vs those with normal hepatic function. METHODS In this multicentre, open-label, parallel-group trial (sponsor Novo Nordisk, ClinicalTrials.gov ID NCT02210871), four groups of participants with normal hepatic function (n = 19) or mild (n = 8), moderate (n = 10) or severe (n = 7) hepatic impairment received a single, subcutaneous dose of 0.5 mg semaglutide. Semaglutide plasma concentrations were assessed frequently for 35 days after dosing. The primary endpoint was area under the semaglutide plasma concentration-time curve from time zero to infinity (AUC0-∞ ). No effect of hepatic impairment was declared if the 90% confidence interval (CI) for the between-group ratio (hepatic impairment/normal function) was within the interval 0.70 to 1.43. RESULTS Semaglutide exposure was similar across all groups, with AUC0-∞ treatment ratios for mild impairment/normal function of 0.95 (90% CI 0.77, 1.16), moderate impairment/normal function 1.02 (90% CI 0.93, 1.12), and severe impairment/normal function 0.97 (90% CI 0.84, 1.12). The maximum plasma semaglutide concentration (Cmax ) did not appear to be influenced by hepatic function, with mild impairment/normal function treatment ratios of 0.99 (90% CI 0.80, 1.23), moderate impairment/normal function 1.02 (90% CI 0.88, 1.18) and severe impairment/normal function 1.15 (90% CI 0.89, 1.48; sensitivity analysis excluding one extreme semaglutide concentration: 1.05 [90% CI 0.88, 1.25]). In all, 10 participants reported 12 mild or moderate non-serious adverse events. No unexpected safety or tolerability issues were observed. CONCLUSIONS Semaglutide exposure did not appear to be affected by hepatic impairment, suggesting that dose adjustment may not be necessary in patients with hepatic impairment. Semaglutide was well tolerated and there were no unexpected safety issues.
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Affiliation(s)
| | - Viera Kupcova
- 3rd Department of Internal MedicineDérer's HospitalBratislavaSlovakia
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Wang J, Wang X, Zhang ZY, Arora S, Lu S, Kansra V. Pharmacokinetics of Rolapitant in Patients With Mild to Moderate Hepatic Impairment. J Clin Pharmacol 2018; 58:686-693. [PMID: 29329482 DOI: 10.1002/jcph.1066] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 11/21/2017] [Indexed: 11/06/2022]
Abstract
Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. This was a phase 1 open-label, parallel-group pharmacokinetic and safety study of a single oral dose of 180 mg of rolapitant and its major active metabolite, M19, in subjects with mild and moderate hepatic impairment compared with healthy matched controls. Pharmacokinetics were assessed by a mixed-model analysis of variance of log-transformed values for maximum observed plasma concentration (Cmax ), observed time at Cmax (tmax ), area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC0-t ), and AUC from time 0 to 120 hours (AUC0-120 ), with hepatic group as a fixed effect. Mean rolapitant Cmax , AUC0-t , and AUC0-120 were similar in the mild hepatic impairment and healthy control groups. In subjects with moderate hepatic impairment, AUC0-t was similar and Cmax was 25% lower than in healthy controls. Mean M19 Cmax and AUC0-t were similar in the mild hepatic impairment group and healthy controls, but <20% lower in those with moderate hepatic impairment versus healthy controls. Fraction of unbound rolapitant was comparable in all groups for rolapitant and M19. Rolapitant was well tolerated in all groups, without serious adverse events. Pharmacokinetic differences between healthy subjects and those with mild or moderate hepatic impairment are unlikely to pose a safety risk and do not warrant predefined dosage adjustment in the presence of hepatic impairment.
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Jacobsen LV, Flint A, Olsen AK, Ingwersen SH. Liraglutide in Type 2 Diabetes Mellitus: Clinical Pharmacokinetics and Pharmacodynamics. Clin Pharmacokinet 2017; 55:657-72. [PMID: 26597252 PMCID: PMC4875959 DOI: 10.1007/s40262-015-0343-6] [Citation(s) in RCA: 142] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liraglutide is an acylated glucagon-like peptide-1 analogue with 97 % amino acid homology with native glucagon-like peptide-1 and greatly protracted action. It is widely used for the treatment of type 2 diabetes mellitus, and administered by subcutaneous injection once daily. The pharmacokinetic properties of liraglutide enable 24-h exposure coverage, a requirement for 24-h glycaemic control with once-daily dosing. The mechanism of protraction relates to slowed release from the injection site, and a reduced elimination rate owing to metabolic stabilisation and reduced renal filtration. Drug exposure is largely independent of injection site, as well as age, race and ethnicity. Increasing body weight and male sex are associated with reduced concentrations, but there is substantial overlap between subgroups; therefore, dose escalation should be based on individual treatment outcome. Exposure is reduced with mild, moderate or severe renal or hepatic impairment. There are no clinically relevant changes in overall concentrations of various drugs (e.g. paracetamol, atorvastatin, griseofulvin, digoxin, lisinopril and oral combination contraceptives) when co-administered with liraglutide. Pharmacodynamic studies show multiple beneficial actions with liraglutide, including improved fasting and postprandial glycaemic control (mediated by increased insulin and reduced glucagon levels and minor delays in gastric emptying), reduced appetite and energy intake, and effects on postprandial lipid profiles. The counter-regulatory hormone response to hypoglycaemia is largely unaltered. The effects of liraglutide on insulin and glucagon secretion are glucose dependent, and hence the risk of hypoglycaemia is low. The pharmacokinetic and pharmacodynamic properties of liraglutide make it an important treatment option for many patients with type 2 diabetes.
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Affiliation(s)
- Lisbeth V Jacobsen
- Clinical Pharmacology, Global Development, Novo Nordisk A/S, Vandtårnsvej 108-110, Søborg, 2860, Copenhagen, Denmark
| | - Anne Flint
- Clinical Pharmacology, Global Development, Novo Nordisk A/S, Vandtårnsvej 108-110, Søborg, 2860, Copenhagen, Denmark
| | - Anette K Olsen
- NCD Project Management, Non-clinical Development, Novo Nordisk A/S, Copenhagen, Denmark
| | - Steen H Ingwersen
- Clinical Pharmacology, Global Development, Novo Nordisk A/S, Vandtårnsvej 108-110, Søborg, 2860, Copenhagen, Denmark.
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Mader JK, Jensen L, Ingwersen SH, Christiansen E, Heller S, Pieber TR. Pharmacokinetic Properties of Liraglutide as Adjunct to Insulin in Subjects with Type 1 Diabetes Mellitus. Clin Pharmacokinet 2017; 55:1457-1463. [PMID: 27282158 PMCID: PMC5069309 DOI: 10.1007/s40262-016-0413-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background The pharmacokinetic properties of liraglutide, a glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes mellitus (T2D), have been established in healthy individuals and subjects with T2D. Liraglutide has been under investigation as adjunct treatment to insulin in type 1 diabetes mellitus (T1D). This single-center, double-blind, placebo-controlled, crossover, clinical pharmacology trial is the first to analyze the pharmacokinetic properties of liraglutide as add-on to insulin in T1D. Methods Subjects (18–64 years; body mass index 20.0–28.0 kg/m2; glycated hemoglobin ≤9.5 %) were randomized 1:1:1 to 0.6, 1.2, or 1.8 mg liraglutide/placebo. Each group underwent two 4-week treatment periods (liraglutide then placebo or placebo then liraglutide) separated by a 2- to 3-week washout. Both trial drugs were administered subcutaneously, once daily, as adjunct to insulin. A stepwise hypoglycemic clamp was performed at the end of each treatment period (data reported previously). Pharmacokinetic endpoints were derived from liraglutide concentration–time curves after the final dose and exposure was compared with data from previous trials in healthy volunteers and subjects with T2D. Results The pharmacokinetic properties of liraglutide in T1D were comparable with those observed in healthy volunteers and subjects with T2D. Area under the steady-state concentration–time curve (AUC) and maximum plasma concentration data were consistent with dose proportionality of liraglutide. Comparison of dose-normalized liraglutide AUC suggested that exposure in T1D, when administered with insulin, is comparable with that observed in T2D. Conclusions Liraglutide, administered as adjunct to insulin in subjects with T1D, shows comparable pharmacokinetics to those in subjects with T2D. ClinicalTrials.gov Identifier: NCT01536665.
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Affiliation(s)
- Julia K Mader
- Division of Endocrinology and Diabetology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Lene Jensen
- Division of Medicine and Science, Novo Nordisk A/S, Søborg, Denmark
| | | | | | - Simon Heller
- Academic Unit of Diabetes, Endocrinology and Metabolism, University of Sheffield, Sheffield, UK
| | - Thomas R Pieber
- Division of Endocrinology and Diabetology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
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Kyhl K, Lønborg J, Hartmann B, Kissow H, Poulsen SS, Ali HE, Kjær A, Dela F, Engstrøm T, Treiman M. Lack of effect of prolonged treatment with liraglutide on cardiac remodeling in rats after acute myocardial infarction. Peptides 2017; 93:1-12. [PMID: 28460895 DOI: 10.1016/j.peptides.2017.04.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Revised: 03/28/2017] [Accepted: 04/27/2017] [Indexed: 02/06/2023]
Abstract
Following the acute phase of a myocardial infarction, a set of structural and functional changes evolves in the myocardium, collectively referred to as cardiac remodeling. This complex set of processes, including interstitial fibrosis, inflammation, myocyte hypertrophy and apoptosis may progress to heart failure. Analogs of the incretin hormone glucagon-like peptide 1 (GLP-1) have shown some promise as cardioprotective agents. We hypothesized that a long-acting GLP-1 analog liraglutide would ameliorate cardiac remodeling over the course of 4 weeks in a rat model of non-reperfused myocardial infarction. In 134 male Sprague Dawley rats myocardial infarctions were induced by ligation of the left anterior descending coronary artery. Rats were randomized to either subcutaneous injection of placebo or 0.3mg liraglutide once daily. Cardiac magnetic resonance imaging was performed after 4 weeks. Histology of the infarcted and remote non-infarcted myocardium, selected molecular remodeling markers and mitochondrial respiration in fibers of remote non-infarcted myocardium were analyzed. Left ventricular end diastolic volume increased in the infarcted hearts by 62% (from 0.58±0.03mL to 0.95±0.07mL, P<0.05) compared to sham operated hearts and left ventricle ejection fraction decreased by 37% (63±1%-40±3%, P<0.05). Increased interstitial fibrosis and phosphorylation of p38 Mitogen Activated Protein Kinase were observed in the non-infarct regions. Mitochondrial fatty acid oxidation was impaired. Liraglutide did not affect any of these alterations. Four-week treatment with liraglutide did not affect cardiac remodeling following a non-reperfused myocardial infarction, as assessed by cardiac magnetic resonance imaging, histological and molecular analysis and measurements of mitochondrial respiration.
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Affiliation(s)
- Kasper Kyhl
- Department of Cardiology, Rigshospitalet; University Hospital of Copenhagen, Denmark; Department of Biomedical Sciences and The Danish National Research Foundation Centre for Heart Arrhythmia, University of Copenhagen, Denmark.
| | - Jacob Lønborg
- Department of Cardiology, Rigshospitalet; University Hospital of Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences and The Danish National Research Foundation Centre for Heart Arrhythmia, University of Copenhagen, Denmark; Department of Biomedical Sciences and Novo Nordisk Foundation Center of Basic Metabolic Research, University of Copenhagen, Denmark
| | - Hannelouise Kissow
- Department of Biomedical Sciences and The Danish National Research Foundation Centre for Heart Arrhythmia, University of Copenhagen, Denmark; Department of Biomedical Sciences and Novo Nordisk Foundation Center of Basic Metabolic Research, University of Copenhagen, Denmark
| | - Steen Seier Poulsen
- Department of Biomedical Sciences and The Danish National Research Foundation Centre for Heart Arrhythmia, University of Copenhagen, Denmark
| | - Henrik El Ali
- Department of Biomedical Sciences and The Danish National Research Foundation Centre for Heart Arrhythmia, University of Copenhagen, Denmark
| | - Andreas Kjær
- Department of Biomedical Sciences and The Danish National Research Foundation Centre for Heart Arrhythmia, University of Copenhagen, Denmark; Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Denmark
| | - Flemming Dela
- Department of Biomedical Sciences and The Danish National Research Foundation Centre for Heart Arrhythmia, University of Copenhagen, Denmark; Xlab, Center for Healthy Aging, Department of Biomedical Sciences, University of Copenhagen, Denmark
| | - Thomas Engstrøm
- Department of Cardiology, Rigshospitalet; University Hospital of Copenhagen, Denmark
| | - Marek Treiman
- Department of Biomedical Sciences and The Danish National Research Foundation Centre for Heart Arrhythmia, University of Copenhagen, Denmark
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Gangopadhyay KK, Singh P. Consensus Statement on Dose Modifications of Antidiabetic Agents in Patients with Hepatic Impairment. Indian J Endocrinol Metab 2017; 21:341-354. [PMID: 28459036 PMCID: PMC5367241 DOI: 10.4103/ijem.ijem_512_16] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Liver disease is an important cause of mortality in type 2 diabetes mellitus (T2DM). It is estimated that diabetes is the most common cause of liver disease in the United States. Virtually, entire spectrum of liver disease is seen in T2DM including abnormal liver enzymes, nonalcoholic fatty liver disease, cirrhosis, hepatocellular carcinoma, and acute liver failure. The treatment of diabetes mellitus (DM) in cirrhotic patients has particular challenges as follows: (1) about half the patients have malnutrition; (2) patients already have advanced liver disease when clinical DM is diagnosed; (3) most of the oral antidiabetic agents (ADAs) are metabolized in the liver; (4) patients often have episodes of hypoglycemia. The aim of this consensus group convened during the National Insulin Summit 2015, Puducherry, was to focus on the challenges with glycemic management, with particular emphasis to safety of ADAs across stages of liver dysfunction. Published literature, product labels, and major clinical guidelines were reviewed and summarized. The drug classes included are biguanides (metformin), the second- or third-generation sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and currently available insulins. Consensus recommendations have been drafted for glycemic targets and dose modifications of all ADAs. These can aid clinicians in managing patients with diabetes and liver disease.
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Affiliation(s)
| | - Parminder Singh
- Division of Endocrinology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
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Abstract
Since 1990, the prevalence of obesity has been steadily increasing in the United States. Over the past four years, new medications have become approved and available, allowing for more options in the management of chronic weight loss among overweight or obese patients. This review article summarizes the efficacy, safety, and clinical attributes of liraglutide among overweight or obese patients with or without comorbidities. Areas covered: A MEDLINE search, from 1970 to June 2016, was conducted using key terms-glucagon-like peptide-1 receptor agonist, liraglutide, overweight, and obesity. Published clinical trials, in the English-language and with primary endpoints related to weight loss, were reviewed and critiqued in this article. Expert commentary: Available as a subcutaneous daily injection, liraglutide is the first glucagon-like peptide-1 (GLP-1) receptor agonist indicated for obesity management, as adjunct therapy with lifestyle and behavioral modifications. Liraglutide 3 mg daily has been associated with greater weight loss than placebo or orlistat in patients without type 2 diabetes. Additionally, liraglutide has resulted in reductions in waist circumference, systolic and diastolic blood pressure, and improvements in lipid panel among overweight and obese patients with and without type 2 diabetes.
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Affiliation(s)
- Katherine G Moore
- a Department of Pharmacy Practice , Presbyterian College School of Pharmacy , Clinton , SC , USA
| | - Kayce Shealy
- a Department of Pharmacy Practice , Presbyterian College School of Pharmacy , Clinton , SC , USA
| | - Jennifer N Clements
- a Department of Pharmacy Practice , Presbyterian College School of Pharmacy , Clinton , SC , USA
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Nauck M. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab 2016; 18:203-16. [PMID: 26489970 PMCID: PMC4785614 DOI: 10.1111/dom.12591] [Citation(s) in RCA: 299] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 10/12/2015] [Accepted: 10/17/2015] [Indexed: 12/26/2022]
Abstract
Over the last few years, incretin-based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon-like peptide 1 (GLP-1), which is partly responsible for augmenting glucose-dependent insulin secretion in response to nutrient intake (the 'incretin effect'). In patients with T2D, pharmacological doses/concentrations of GLP-1 can compensate for the inability of diabetic β cells to respond to the main incretin hormone glucose-dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin-based glucose-lowering medications. Two classes of incretin-based therapies are available: GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1RAs promote GLP-1 receptor (GLP-1R) signalling by providing GLP-1R stimulation through 'incretin mimetics' circulating at pharmacological concentrations, whereas DPP-4 inhibitors prevent the degradation of endogenously released GLP-1. Both agents produce reductions in plasma glucose and, as a result of their glucose-dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non-glycaemic benefits such as weight loss, improvements in β-cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin-based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients.
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Affiliation(s)
- M Nauck
- Division of Diabetology, Medical Department I, St. Josef Hospital (Ruhr University Bochum), Bochum, Germany
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Scheen AJ. Pharmacokinetics in patients with chronic liver disease and hepatic safety of incretin-based therapies for the management of type 2 diabetes mellitus. Clin Pharmacokinet 2015; 53:773-85. [PMID: 25091053 DOI: 10.1007/s40262-014-0157-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Patients with type 2 diabetes mellitus have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis, and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type 2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarises the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and their hepatic safety was carefully analysed in large clinical trials. Only mild changes in pharmacokinetic characteristics of DPP-4 inhibitors were observed in patients with different degrees of HI, presumably without major clinical relevance. GLP-1 receptor agonists have a renal excretion rather than liver metabolism. Specific pharmacokinetic data in patients with HI are only available for liraglutide. No significant changes in liver enzymes were reported with DPP-4 inhibitors or GLP-1 receptor agonists, alone or in combination with various other glucose-lowering agents, in clinical trials up to 2 years in length. On the contrary, preliminary data suggested that incretin-based therapies may be beneficial in patients with CLD, more particularly in the presence of non-alcoholic fatty liver disease. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, because of a lack of clinical experience with incretin-based therapies in these vulnerable patients.
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Affiliation(s)
- André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, University of Liège, Liège, Belgium,
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Young MA, Wald JA, Matthews JE, Scott R, Hodge RJ, Zhi H, Reinhardt RR. Clinical Pharmacology of Albiglutide, a GLP-1 Receptor Agonist. Postgrad Med 2015; 126:84-97. [DOI: 10.3810/pgm.2014.11.2836] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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Chalmer T, Almdal TP, Vilsbøll T, Knop FK. Adverse drug reactions associated with the use of liraglutide in patients with type 2 diabetes--focus on pancreatitis and pancreas cancer. Expert Opin Drug Saf 2014; 14:171-80. [PMID: 25363438 DOI: 10.1517/14740338.2015.975205] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide , is a widely used drug for the treatment of type 2 diabetes. Liraglutide is one of several incretin-based agents that have been suggested to be associated with pancreatitis and pancreas cancer. The suspicion accelerated after publication of an autopsy study claiming increased incidences of several pathological changes in pancreata from patients with diabetes treated with incretin-based drugs. AREAS COVERED The aim of the present review is to give an overview of the pharmacology of liraglutide and provide a review of adverse reactions associated with liraglutide with a focus on the risk of pancreatitis and pancreas cancer. EXPERT OPINION When comprehensively reviewing the available literature, no clear and significant associations between liraglutide and pancreatitis and/or pancreas cancer seem evident. However, a recently published analysis suggests a trend toward a slightly elevated risk of pancreatitis with GLP-1 receptor agonists (including liraglutide), which may become statistical significant as more data become available. Well-established side effects are of gastrointestinal origin, typical mild-to-moderate and of transient character. The risk of hypoglycemia associated with liraglutide treatment is low.
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Affiliation(s)
- Thor Chalmer
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen , Hellerup , Denmark
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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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Scheen AJ. Pharmacokinetic and toxicological considerations for the treatment of diabetes in patients with liver disease. Expert Opin Drug Metab Toxicol 2014; 10:839-57. [PMID: 24669954 DOI: 10.1517/17425255.2014.902444] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Patients with type 2 diabetes have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents may be a cause for concern in the case of hepatic impairment (HI). AREAS COVERED An extensive literature search was performed to analyze the influence of HI on the pharmacokinetics (PK) of glucose-lowering agents and the potential consequences for clinical practice as far as the efficacy/safety balance of their use in diabetic patients with CLD is concerned. EXPERT OPINION Almost no PK studies have been published regarding metformin, sulfonylureas, thiazolidinediones and α-glucosidase inhibitors in patients with HI. Only mild changes in PK of glinides, dipeptidyl peptidase-4 inhibitors and sodium glucose cotransporters type 2 inhibitors were observed in dedicated PK studies in patients with various degrees of HI, presumably without major clinical relevance although large clinical experience is lacking. Glucagon-like peptide-1 receptor agonists have a renal excretion rather than liver metabolism. Rare anecdotal case reports of hepatotoxicity have been described with various glucose-lowering agents contrasting with numerous reassuring data. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, including with the use of metformin.
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Affiliation(s)
- André J Scheen
- University of Liège, CHU Sart Tilman (B35), Center for Interdisciplinary Research on Medicines (CIRM), Division of Diabetes, Nutrition and Metabolic Disorders and Division of Clinical Pharmacology, Department of Medicine , B-4000 Liege 1 , Belgium +32 4 3667238 ; +32 4 3667068 ;
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Abstract
Type 2 diabetes is characterized by a progressive decline in beta cell function, with consequent worsening of glycemic control. The ideal antihyperglycemic treatment should achieve good and sustained glycemic control, with a low risk of hypoglycemia and no weight gain. This paper reviews the efficacy and tolerability of liraglutide, a glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes. Once-daily injection of liraglutide (at doses of 1.2 mg and 1.8 mg), as monotherapy or in combination with one or two oral antihyperglycemic agents, was associated with greater improvements in glycemic control compared with active comparators or placebo in several controlled, randomized Phase III trials, including the six trials of the LEAD (Liraglutide Effect and Action in Diabetes) program. Liraglutide also improved beta cell function, body weight, systolic blood pressure, and lipid profile, thereby achieving many of the goals of ideal antihyperglycemic therapy. Liraglutide was generally well tolerated in the Phase III trials. The most common adverse events were nausea, vomiting, and diarrhea, usually of mild to moderate intensity. The observed rate of pancreatitis was low and comparable with that of the general diabetic population. In conclusion, although most trials were relatively short and focused on surrogate endpoints, liraglutide emerges as an effective and well tolerated treatment for type 2 diabetes, carrying a low risk of hypoglycemia, weight loss, and possible reduction of cardiovascular risk.
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Affiliation(s)
- Mauro Rigato
- Department of Medicine, University Hospital of Padova, Padova, Italy
| | - Gian Paolo Fadini
- Department of Medicine, University Hospital of Padova, Padova, Italy
- Correspondence: Gian Paolo Fadini, Department of Medicine, University of Padova, Via Giustiniani 2, 35100 Padova, Italy, Tel +39 04 9821 4318, Fax +39 04 9821 2184, Email
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Plum A, Jensen LB, Kristensen JB. In vitro protein binding of liraglutide in human plasma determined by reiterated stepwise equilibrium dialysis. J Pharm Sci 2013; 102:2882-8. [PMID: 23853127 PMCID: PMC3838623 DOI: 10.1002/jps.23648] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Revised: 06/04/2013] [Accepted: 06/10/2013] [Indexed: 12/25/2022]
Abstract
Liraglutide is a human glucagon-like peptide-1 (GLP-1) analogue approved for the treatment of type 2 diabetes. It is based on human GLP-1 with the addition of a 16-carbon fatty acid, which facilitates binding to plasma proteins, thus prolonging the elimination half-life and allowing once-daily administration. It has not been possible to quantify liraglutide protein binding by ultrafiltration (the usual method of choice), as the lipophilic molecule becomes trapped in the filter membrane. Therefore, the aim of this study was to develop a methodology that could determine the extent of liraglutide binding to plasma proteins in vitro. We report here the details of a novel reiterated stepwise equilibrium dialysis assay that has successfully been used to quantify liraglutide plasma protein binding. The assay allowed quantification of liraglutide binding to proteins in purified plasma protein solutions and human plasma samples and was effective at plasma dilutions as low as 5%. At a clinically relevant liraglutide concentration (10(4) pM), greater than 98.9% of liraglutide was bound to protein. Specific binding to human serum albumin and α1-acid glycoprotein was 99.4% and 99.3%, respectively. The novel methodology described herein could have an application in the quantification of plasma protein binding of other highly lipophilic drug molecules.
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Affiliation(s)
- Anne Plum
- Department of Diabetes Pharmacology PK/PD, Novo Nordisk A/S, Måløv DK-2760, Denmark.
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Schwartz SS. A practice-based approach to the 2012 position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Curr Med Res Opin 2013; 29:793-9. [PMID: 23614630 DOI: 10.1185/03007995.2013.798637] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The position statement on the management of hyperglycemia in patients with type 2 diabetes mellitus issued in 2012 by the American Diabetes Association and the European Association for the Study of Diabetes contains significant improvements over the 2009 version, including an emphasis on patient-centered care, enhanced strategies for lifestyle modification, a focus on comprehensive cardiovascular risk reduction, and increased pharmacotherapy choices. As diabetes management evolves over time, further improvements may be made in future consensus statements, including a focus on prevention and early treatment and improved glycemic control in all patients, including those with comorbidities. These goals will be achievable by waning use of therapies known to cause hypoglycemia and weight gain and the increased use of therapies that do not carry these risks.
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Rizzo M, Nikolic D, Banach M, Giglio RV, Patti AM, Di Bartolo V, Tamburello A, Zabbara A, Pecoraro G, Montalto G, Rizvi AA. The effects of liraglutide on glucose, inflammatory markers and lipoprotein metabolism: current knowledge and future perspective. ACTA ACUST UNITED AC 2013. [DOI: 10.2217/clp.13.8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Montanya E. A comparison of currently available GLP-1 receptor agonists for the treatment of type 2 diabetes. Expert Opin Pharmacother 2012; 13:1451-67. [PMID: 22725703 DOI: 10.1517/14656566.2012.692777] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Glucagon-like peptide-1 (GLP-1) receptor agonists are a valuable addition to the type 2 diabetes armamentarium. They increase insulin secretion and reduce glucagon secretion in a glucose-dependent manner, posing a relatively low hypoglycemia risk. GLP-1 receptor agonists also offer weight-loss benefits. Because GLP-1 receptor agonists are relatively new agents, there is limited direction on their use. AREAS COVERED This article aims to provide guidance to physicians when considering GLP-1 receptor agonist use in individual patients. It examines the clinical profiles of the currently available GLP-1 receptor agonists: exenatide twice-daily (BID), liraglutide once daily and exenatide extended release (ER) once weekly. Phase III clinical trial data on efficacy, safety and patient satisfaction are compared, with a primary focus on head-to-head trials. EXPERT OPINION Liraglutide seems to be the most effective GLP-1 receptor agonist in terms of HbA(1c) reduction and weight loss. Exenatide BID may offer an advantage where postprandial glucose control is a primary concern. Exenatide ER generally outperforms exenatide BID and is a good option for patients who struggle to adhere to more frequent regimens. The future may hold interesting developments in terms of reduced dosing frequency, oral formulations and alternative therapeutic uses.
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Affiliation(s)
- Eduard Montanya
- Endocrine Unit, Hospital Universitari Bellvitge-IDIBELL, Barcelona, Spain.
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Perry CM. Liraglutide: a review of its use in the management of type 2 diabetes mellitus. Drugs 2012; 71:2347-73. [PMID: 22085389 DOI: 10.2165/11208110-000000000-00000] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Liraglutide (Victoza®) is a subcutaneously administered glucagon-like peptide-1 (GLP-1) receptor agonist produced by recombinant DNA technology and used as an adjunct to diet and exercise in the treatment of adults with type 2 diabetes mellitus. This article reviews the clinical efficacy and tolerability of liraglutide in adults with type 2 diabetes, and provides a summary of its pharmacological properties. Recently published pharmacoeconomic studies of liraglutide are also reviewed. Administered subcutaneously, liraglutide (usually 1.2 or 1.8 mg once daily) generally produced greater improvements in glycaemic control than active comparators or placebo when administered as monotherapy or in combination with one or two oral antidiabetic drugs (OADs) to adults with type 2 diabetes in numerous randomized, controlled phase III trials. These included six trials in the LEAD trial programme that was designed to evaluate the efficacy and safety of liraglutide across a continuum of antihyperglycaemic management for patients with type 2 diabetes. Liraglutide was generally well tolerated, with a low risk of hypoglycaemia evident, in the phase III trials. The most common adverse events were gastrointestinal and included nausea and diarrhoea; most events were mild to moderate in severity and decreased in incidence over time. In conclusion, liraglutide has an important place in the management of adults with type 2 diabetes across a continuum of care. As well as providing effective glycaemic control, liraglutide improves pancreatic β-cell function and leads to bodyweight loss, thereby addressing some of the unmet needs of patients treated with traditional OADs.
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Abstract
Liraglutide is a United States Food and Drug Administration (FDA)-approved glucagon-like peptide-1 (GLP-1) analog that is 97% homologous to native human GLP-1. The additional 16-carbon fatty acid chain causes noncovalent binding to albumin, which slows absorption from the injection site and protects the molecule from degradation by the enzyme dipeptidyl peptidase-4, allowing for protraction of action. Albumin binding and an elimination half-life of 13 hours combine to allow for once-daily dosing. Liraglutide 1.2 and 1.8 mg/day given as monotherapy for up to 52 weeks produced mean reductions in hemoglobin A1c (A1C) of 0.6-1.6%; combination therapy of liraglutide with oral antidiabetic agents demonstrated mean A1C reductions up to 1.5%. The satiety effect of GLP-1 receptor agonists and documented weight loss as great as 3.38 kg in clinical trials may make liraglutide ideal for obese patients with type 2 diabetes mellitus. Like other incretin-based agents, preliminary studies suggest liraglutide may also increase β-cell mass and function. Hypoglycemia is rare with liraglutide and tends to occur when used in combination with sulfonylureas; liraglutide in combination with insulin is not yet FDA approved. The pharmacokinetic parameters of liraglutide are unaffected by age, sex, race, or ethnicity, and no special recommendations for altered dosing of liraglutide need apply to populations with hepatic or renal impairment. Results from clinical trials have not shown an increased risk of medullary thyroid cancer, pancreatitis, or poor cardiovascular outcomes with liraglutide treatment. Ongoing, long-term monitoring studies continue to evaluate the safety of liraglutide treatment in these outcomes.
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Affiliation(s)
- Evan M Sisson
- 1 Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia 23298-0533, USA.
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Brice KR, Tzefos MK. The Clinical Efficacy and Safety of Glucagon-Like Peptide-1 (GLP-1) Agonists in Adults with Type 2 Diabetes Mellitus. CLINICAL MEDICINE INSIGHTS-ENDOCRINOLOGY AND DIABETES 2011; 4:13-24. [PMID: 22879790 PMCID: PMC3411513 DOI: 10.4137/cmed.s4086] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Objective: To review the efficacy and safety of glucagon-like peptide-1 (GLP-1) agonists to determine their role in type 2 diabetes mellitus (T2DM). Data sources: A Medline search was conducted using the keywords exenatide, liraglutide, glucagon-like peptide-1, type 2 diabetes mellitus, hyperglycemia, pharmacokinetics, pharmacology and safety. Study selection: All identified articles written in English were evaluated with priority given to controlled, randomized trials including human data. References of identified published trials were reviewed for additional trials to be included in the review. Data synthesis: Exenatide and liraglutide are GLP-1 agonists approved for the treatment of T2DM. Several randomized, active and placebo controlled trials examining the efficacy and safety of exenatide and liraglutide both as monotherapy and in combination therapy have been conducted. Both agents have demonstrated improved glycemic control in addition to weight loss and increased beta-cell function. The most common adverse effects are gastrointestinal in nature and appear to be transient. Conclusion: It appears exenatide and liraglutide are safe and effective in the treatment of T2DM and may exhibit effects that make them preferred over other anti-diabetic medications.
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Affiliation(s)
- Kira R Brice
- Wingate University School of Pharmacy, Campus Box 3087, Wingate, NC 28174, USA
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