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Bodard S, Kharroubi-Lakouas D, Guinebert S, Dariane C, Gillard P, Sakhi H, Ferriere E, Delaye M, Timsit MO, Correas JM, Hélénon O, Boudhabhay I. [Cancer imaging and prevention of renal failure]. Bull Cancer 2024; 111:663-674. [PMID: 36371283 DOI: 10.1016/j.bulcan.2022.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 09/15/2022] [Accepted: 09/20/2022] [Indexed: 11/11/2022]
Abstract
The risk of acute renal failure (ARF) following iodinated contrast media injection has long been overestimated because of the previous use of more toxic ICPs and uncontrolled studies. Nowadays, this concept is being questioned. Patients with severe renal failure and/or ARF are the only group still considered at risk. In these patients, it is necessary to discuss an alternative without an iodinated contrast agent. Contrast-enhanced ultrasound, MRI, spectral CT or PET-CT scan can be used instead of contrast-enhanced CT. Preventive measures should be applied when appropriate substitute to CT is not available or not diagnosed (minimum necessary dose of ICP, interruption of some treatments and prior hydration). These recommendations formalized by the European Society of Urogenital Radiology (ESUR) in 2018 address most situations faced by clinicians. In complex situations, an opinion from a nephrologist remains necessary after asking the radiologist about the availability of acceptable substitutes.
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Affiliation(s)
- Sylvain Bodard
- AP-HP, Hôpital Necker Enfants malades, service d'imagerie adulte, 75015 Paris, France; Université de Paris Cité, 75006 Paris, France; Sorbonne université, CNRS, Inserm, laboratoire d'imagerie biomédicale, Paris, France.
| | | | - Sylvain Guinebert
- AP-HP, Hôpital Necker Enfants malades, service d'imagerie adulte, 75015 Paris, France; Université de Paris Cité, 75006 Paris, France
| | - Charles Dariane
- Université de Paris Cité, 75006 Paris, France; AP-HP, hôpital européen Georges Pompidou, service d'urologie, 75015 Paris, France
| | - Paul Gillard
- AP-HP, Hôpital Necker Enfants malades, service d'imagerie adulte, 75015 Paris, France
| | - Hamza Sakhi
- Université de Paris Cité, 75006 Paris, France; AP-HP, hôpital Necker Enfants malades, service de néphrologie et transplantation rénale adulte, 75015 Paris, France
| | - Elsa Ferriere
- Université de Paris Cité, 75006 Paris, France; AP-HP, hôpital Necker Enfants malades, service de néphrologie et transplantation rénale adulte, 75015 Paris, France
| | - Matthieu Delaye
- Institut curie, université Versailles Saint-Quentin, département d'oncologie médicale, Saint-Cloud, France; Groupe de Recherche Interdisciplinaire Francophone en Onco-Néphrologie (GRIFON), Paris, France
| | - Marc-Olivier Timsit
- Université de Paris Cité, 75006 Paris, France; AP-HP, hôpital européen Georges Pompidou, service d'urologie, 75015 Paris, France
| | - Jean-Michel Correas
- AP-HP, Hôpital Necker Enfants malades, service d'imagerie adulte, 75015 Paris, France; Université de Paris Cité, 75006 Paris, France
| | - Olivier Hélénon
- AP-HP, Hôpital Necker Enfants malades, service d'imagerie adulte, 75015 Paris, France; Université de Paris Cité, 75006 Paris, France
| | - Idris Boudhabhay
- Université de Paris Cité, 75006 Paris, France; AP-HP, hôpital Necker Enfants malades, service de néphrologie et transplantation rénale adulte, 75015 Paris, France
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See KC. Metformin-associated lactic acidosis: A mini review of pathophysiology, diagnosis and management in critically ill patients. World J Diabetes 2024; 15:1178-1186. [PMID: 38983827 PMCID: PMC11229964 DOI: 10.4239/wjd.v15.i6.1178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 04/04/2024] [Accepted: 04/23/2024] [Indexed: 06/11/2024] Open
Abstract
Metformin is a common diabetes drug that may reduce lactate clearance by inhibiting mitochondrial oxidative phosphorylation, leading to metformin-associated lactic acidosis (MALA). As diabetes mellitus is a common chronic metabolic condition found in critically ill patients, pre-existing metformin use can often be found in critically ill patients admitted to the intensive care unit or the high dependency unit. The aim of this narrative mini review is therefore to update clinicians about MALA, and to provide a practical approach to its diagnosis and treatment. MALA in critically ill patients may be suspected in a patient who has received metformin and who has a high anion gap metabolic acidosis, and confirmed when lactate exceeds 5 mmol/L. Risk factors include those that reduce renal elimination of metformin (renal impairment from any cause, histamine-2 receptor antagonists, ribociclib) and excessive alcohol consumption (as ethanol oxidation consumes nicotinamide adenine dinucleotides that are also required for lactate metabolism). Treatment of MALA involves immediate cessation of metformin, supportive management, treating other concurrent causes of lactic acidosis like sepsis, and treating any coexisting diabetic ketoacidosis. Severe MALA requires extracorporeal removal of metformin with either intermittent hemodialysis or continuous kidney replacement therapy. The optimal time to restart metformin has not been well-studied. It is nonetheless reasonable to first ensure that lactic acidosis has resolved, and then recheck the kidney function post-recovery from critical illness, ensuring that the estimated glomerular filtration rate is 30 mL/min/1.73 m2 or better before restarting metformin.
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Affiliation(s)
- Kay Choong See
- Department of Medicine, National University Hospital, Singapore 119228, Singapore
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Abstract
PURPOSE OF REVIEW This review provides the most recent update of metformin, a biguanide oral antihyperglycemic drug used as a first-line treatment in type 2 diabetes mellitus. RECENT FINDINGS Metformin continues to dominate in the world of antidiabetics, and its use will continue to rise because of its high efficiency and easy availability. Apart from type 2 diabetes, research is exploring its potential in other conditions such as cancer, memory loss, bone disorders, immunological diseases, and aging. Metformin is the most prescribed oral antidiabetic worldwide. It has been in practical use for the last six decades and continues to be the preferred drug for newly diagnosed type 2 diabetes mellitus. It reduces glucose levels by decreasing hepatic glucose production, reducing intestinal glucose absorption, and increasing insulin sensitivity. It can be used as monotherapy or combined with other antidiabetics like sulfonylureas, DPP-4 inhibitors, SGLT-2 inhibitors, or insulin, improving its efficacy. Metformin can be used once or twice daily, depending on requirements. Prolonged usage of metformin may lead to abdominal discomfort, deficiency of Vitamin B12, or lactic acidosis. It should be used carefully in patients with renal impairment. Recent studies have explored additional benefits of metformin in polycystic ovarian disease, gestational diabetes mellitus, cognitive disorders, and immunological diseases. However, more extensive studies are needed to confirm these additional benefits.
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Harada M, Han S, Shi M, Ge J, Yu S, Adam J, Adamski J, Scheerer MF, Neschen S, de Angelis MH, Wang-Sattler R. Metabolic effects of SGLT2i and metformin on 3-hydroxybutyric acid and lactate in db/db mice. Int J Biol Macromol 2024; 265:130962. [PMID: 38503370 DOI: 10.1016/j.ijbiomac.2024.130962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 03/15/2024] [Accepted: 03/15/2024] [Indexed: 03/21/2024]
Abstract
Combining a Sodium-Glucose-Cotransporter-2-inhibitor (SGLT2i) with metformin is recommended for managing hyperglycemia in patients with type 2 diabetes (T2D) who have cardio-renal complications. Our study aimed to investigate the metabolic effects of SGLT2i and metformin, both individually and synergistically. We treated leptin receptor-deficient (db/db) mice with these drugs for two weeks and conducted metabolite profiling, identifying 861 metabolites across kidney, liver, muscle, fat, and plasma. Using linear regression and mixed-effects models, we identified two SGLT2i-specific metabolites, X-12465 and 3-hydroxybutyric acid (3HBA), a ketone body, across all examined tissues. The levels of 3HBA were significantly higher under SGLT2i monotherapy compared to controls and were attenuated when combined with metformin. We observed similar modulatory effects on metabolites involved in protein catabolism (e.g., branched-chain amino acids) and gluconeogenesis. Moreover, combination therapy significantly raised pipecolate levels, which may enhance mTOR1 activity, while modulating GSK3, a common target of SGLT2i and 3HBA inhibition. The combination therapy also led to significant reductions in body weight and lactate levels, contrasted with monotherapies. Our findings advocate for the combined approach to better manage muscle loss, and the risks of DKA and lactic acidosis, presenting a more effective strategy for T2D treatment.
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Affiliation(s)
- Makoto Harada
- Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Siyu Han
- Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Mengya Shi
- Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Jianhong Ge
- Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Shixiang Yu
- Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Jonathan Adam
- Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Jerzy Adamski
- Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Markus F Scheerer
- Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Susanne Neschen
- Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Martin Hrabe de Angelis
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Chair of Experimental Genetics, School of Life Sciences, Technical University of Munich (TUM), Freising, Germany
| | - Rui Wang-Sattler
- Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
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Quiroz-Aldave JE, Gamarra-Osorio ER, Durand-Vásquez MDC, Rafael-Robles LDP, Gonzáles-Yovera JG, Quispe-Flores MA, Concepción-Urteaga LA, Román-González A, Paz-Ibarra J, Concepción-Zavaleta MJ. From liver to hormones: The endocrine consequences of cirrhosis. World J Gastroenterol 2024; 30:1073-1095. [PMID: 38577191 PMCID: PMC10989500 DOI: 10.3748/wjg.v30.i9.1073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 01/02/2024] [Accepted: 02/06/2024] [Indexed: 03/06/2024] Open
Abstract
Hepatocrinology explores the intricate relationship between liver function and the endocrine system. Chronic liver diseases such as liver cirrhosis can cause endocrine disorders due to toxin accumulation and protein synthesis disruption. Despite its importance, assessing endocrine issues in cirrhotic patients is frequently neglected. This article provides a comprehensive review of the epidemiology, pathophysiology, diagnosis, and treatment of endocrine disturbances in liver cirrhosis. The review was conducted using the PubMed/Medline, EMBASE, and Scielo databases, encompassing 172 articles. Liver cirrhosis is associated with endocrine disturbances, including diabetes, hypoglycemia, sarcopenia, thyroid dysfunction, hypogonadotropic hypogonadism, bone disease, adrenal insufficiency, growth hormone dysfunction, and secondary hyperaldosteronism. The optimal tools for diagnosing diabetes and detecting hypoglycemia are the oral glucose tolerance test and continuous glucose monitoring system, respectively. Sarcopenia can be assessed through imaging and functional tests, while other endocrine disorders are evaluated using hormonal assays and imaging studies. Treatment options include metformin, glucagon-like peptide-1 analogs, sodium-glucose co-transporter-2 inhibitors, and insulin, which are effective and safe for diabetes control. Established standards are followed for managing hypoglycemia, and hormone replacement therapy is often necessary for other endocrine dysfunctions. Liver transplantation can address some of these problems.
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Affiliation(s)
| | | | | | | | | | | | | | - Alejandro Román-González
- Department of Endocrinology, Hospital Universitario de San Vicente Fundación, Medellin 050010, Colombia
- Internal Medicine, Universidad de Antioquia, Medellín 050010, Colombia
| | - José Paz-Ibarra
- School of Medicine, Universidad Nacional Mayor de San Marcos, Lima 15081, Peru
- Department of Endocrinology, Hospital Nacional Edgardo Rebagliati Martins, Lima 15072, Peru
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Deng C, Xie Y, Li J, Jiang H, Niu X, Yan D, Su H, Kuang H, Tian L, Liu J, Jiang S, Quan H, Xu J, Wu X, Tao N, Sun S, Tang X, Chen Y, Fan L, Li X, Zhou Z. Care, control and complications of hospitalised patients with type 1 diabetes in China: A nationwide-based registry study. Diabetes Metab Res Rev 2024; 40:e3796. [PMID: 38529788 DOI: 10.1002/dmrr.3796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/17/2024] [Accepted: 03/11/2024] [Indexed: 03/27/2024]
Abstract
AIMS To evaluate the status quo of type 1 diabetes (T1D) management and characteristics of hospitalised patients with T1D in China through a nationwide multicentre registry study, the China Diabetes Type 1 Study (CD1S). MATERIALS AND METHODS Clinical data from the electronic hospital records of all people with T1D were retrospectively collected in 13 tertiary hospitals across 7 regions of China from January 2016 to December 2021. Patients were defined as newly diagnosed who received a diagnosis of diabetes for less than 3 months. RESULTS Among the 4993 people with T1D, the median age (range) at diagnosis was 23.0 (1.0-87.0) years and the median disease duration was 2.0 years. The median haemoglobin A1c (HbA1c) level was 10.7%. The prevalence of obesity, overweight, dyslipidemia, and hypertension were 2.5%, 10.8%, 62.5% and 25.9%, respectively. The incidence rate of diabetic ketoacidosis at disease onset was 41.1%, with the highest in children <10 years of age (50.6%). In patients not newly diagnosed, 60.7% were diagnosed with at least one chronic diabetic complication, with the highest proportion (45.3%) of diabetic peripheral neuropathy. Chronic complications were detected in 79.2% of people with T1D duration ≥10 years. CONCLUSIONS In the most recent years, there were still unsatisfactory metabolic control and high incidence of diabetic ketoacidosis as well as chronic diabetic complications among inpatients with T1D in China. The ongoing CD1S prospective study aims to improve the quality of T1D management nationally.
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Affiliation(s)
- Chao Deng
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yuting Xie
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Juan Li
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Hongwei Jiang
- Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Xiaohong Niu
- Department of Endocrinology, Changzhi Medical College Affiliated Heji Hospital, Changzhi, China
| | - Dewen Yan
- Department of Endocrinology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen Clinical Research Center for Metabolic Diseases, Shenzhen Center for Diabetes Control and Prevention, Shenzhen, China
| | - Heng Su
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, China
| | - Hongyu Kuang
- The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Liming Tian
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou, China
| | - Jing Liu
- Department of Endocrinology, Gansu Provincial Hospital, Lanzhou, China
| | - Sheng Jiang
- Department of Endocrinology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Huibiao Quan
- Department of Endocrinology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Jixiong Xu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiaohong Wu
- Department of Endocrinology, Geriatric Medicine Center, Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Zhejiang, China
| | - Na Tao
- Department of Endocrinology, The Kunming Children's Hospital, Kunming, China
| | - Shuguang Sun
- Department of Endocrinology, The First Affiliated Hospital of Dali University, Dali, China
| | - Xiaohan Tang
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yan Chen
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Li Fan
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xia Li
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, China
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Clemens KK, Ernst J, Khan T, Reichert S, Khan Q, LaPier H, Chiu M, Stranges S, Sahi G, Castrillon-Ramirez F, Moist L. Glucagon-like peptide 1 receptor agonists in end-staged kidney disease and kidney transplantation: A narrative review. Nutr Metab Cardiovasc Dis 2023; 33:1111-1120. [PMID: 37100640 DOI: 10.1016/j.numecd.2023.03.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/22/2023] [Accepted: 03/27/2023] [Indexed: 04/28/2023]
Abstract
AIMS Glucagon-like peptide 1 receptor agonists (GLP-1RA) improve glycemic control and promote weight loss in type 2 diabetes (DM2) and obesity. We identified studies describing the metabolic benefits of GLP-1RA in end-staged kidney disease (ESKD) and kidney transplantation. DATA SYNTHESIS We searched for randomized controlled trials (RCTs) and observational studies that investigated the metabolic benefits of GLP-1RA in ESKD and kidney transplantation. We summarized the effect of GLP-1RA on measures of obesity and glycemic control, examined adverse events, and explored adherence with therapy. In small RCTs of patients with DM2 on dialysis, liraglutide for up to 12 weeks lowered HbA1c by 0.8%, reduced time in hyperglycemia by ∼2%, lowered blood glucose by 2 mmol/L and reduced weight by 1-2 kg, compared with placebo. In prospective studies inclusive of ESKD, 12 months of semaglutide reduced HbA1c by 0.8%, and contributed to weight losses of 8 kg. In retrospective cohort studies in DM2 and kidney transplantation, 12 months of GLP-1RA lowered HbA1c by 2%, and fasting glucose by ∼3 mmol/L compared with non-use, and in some reports, weight losses of up to 4 kg were described. Gastrointestinal (GI) side effects were most commonly reported, with hypoglycemia described with GLP-1RA in hemodialysis, particularly in those using insulin. CONCLUSIONS GLP-1RA are growing in popularity in those with DM2 and obesity. In small RCTs and observational cohort studies modest glycemic and weight benefits have been described in ESKD and transplantation, but GI side effects may limit adherence. Larger and longer term studies of GLP-1RA remain important.
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Affiliation(s)
- Kristin K Clemens
- Department of Medicine, Division of Endocrinology and Metabolism, Western University, 268 Grosvenor Street, N6A 4V2, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, 1465 Richmond Street, N6G 2M1, London, Ontario, Canada; Centre for Diabetes, Endocrinology and Metabolism, St. Joseph's Health Care London, 268 Grosvenor Street, N6A 4V2, London, Ontario, Canada; ICES Western, 800 Commissioners Road East, N6A 5W9, London, Ontario, Canada; Lawson Health Research Institute, 750 Base Line Road East, Suite 300, N6C 2R5, London, Ontario, Canada; Department of Medicine, Western University, 800 Commissioners Road East, N6A 5W9, London, Ontario, Canada.
| | - Jaclyn Ernst
- Department of Medicine, Western University, 800 Commissioners Road East, N6A 5W9, London, Ontario, Canada
| | - Tayyab Khan
- Department of Medicine, Division of Endocrinology and Metabolism, Western University, 268 Grosvenor Street, N6A 4V2, London, Ontario, Canada; Centre for Diabetes, Endocrinology and Metabolism, St. Joseph's Health Care London, 268 Grosvenor Street, N6A 4V2, London, Ontario, Canada
| | - Sonja Reichert
- Department of Family Medicine, Western University, 1465 Richmond Street, N6G 2M1, London, Ontario, Canada
| | - Qasim Khan
- Department of Medicine, Division of Gastroenterology, Western University, 800 Commissioners Road East, N6A 5W9, London, Ontario, Canada
| | - Heather LaPier
- Centre for Diabetes, Endocrinology and Metabolism, St. Joseph's Health Care London, 268 Grosvenor Street, N6A 4V2, London, Ontario, Canada
| | - Michael Chiu
- Department of Medicine, Division of Nephrology, Western University, 800 Commissioners Road East, N6A 5W9, London, Ontario, Canada
| | - Saverio Stranges
- Department of Epidemiology and Biostatistics, Western University, 1465 Richmond Street, N6G 2M1, London, Ontario, Canada; Department of Medicine, Western University, 800 Commissioners Road East, N6A 5W9, London, Ontario, Canada; Department of Family Medicine, Western University, 1465 Richmond Street, N6G 2M1, London, Ontario, Canada
| | - Gurleen Sahi
- Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, N6A 5C1, London, Ontario, Canada
| | - Fabio Castrillon-Ramirez
- Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, N6A 5C1, London, Ontario, Canada
| | - Louise Moist
- Department of Epidemiology and Biostatistics, Western University, 1465 Richmond Street, N6G 2M1, London, Ontario, Canada; Lawson Health Research Institute, 750 Base Line Road East, Suite 300, N6C 2R5, London, Ontario, Canada; Department of Medicine, Division of Nephrology, Western University, 800 Commissioners Road East, N6A 5W9, London, Ontario, Canada
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Jamaluddin J, Mohamed-Yassin MS, Jamil SN, Mohamed Kamel MA, Yusof MY. Frequency and predictors of inappropriate medication dosages for cardiovascular disease prevention in chronic kidney disease patients: A retrospective cross-sectional study in a Malaysian primary care clinic. Heliyon 2023; 9:e14998. [PMID: 37025791 PMCID: PMC10070146 DOI: 10.1016/j.heliyon.2023.e14998] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 03/20/2023] [Accepted: 03/23/2023] [Indexed: 03/31/2023] Open
Abstract
Patients with chronic kidney disease (CKD) are at increased risk of cardiovascular events. This study aimed to assess the frequency of inappropriate medication dosages (IMD) for cardiovascular disease prevention among patients with CKD and its predictors in an urban academic primary care clinic in Selangor, Malaysia. All patients who attended the clinic from April to June 2019 and fulfilled the inclusion criteria were included in this cross-sectional study, except for those with an estimated glomerular filtration rate (eGFR) of more than 90 ml/min, diagnosed with urinary tract infection, pregnant or were on dialysis for end stage renal disease. Their prescriptions on the electronic medical record (EMR) system were evaluated for appropriateness using the dose adjustment recommendations based on the 2018 Malaysian Clinical Practice Guidelines on management of CKD. A total of 362 medical records were included in this study. 16.6% (95% Confidence Interval [CI]: 12.9-20.8) or 60 out of 362 of the patient records analysed contained medications prescribed with inappropriate dosages. Patients with higher stages of CKD were associated with higher odds of IMD, namely CKD stage G3b (adjusted Odds Ratio [aOR] 10.41; 95% CI: 2.31-46.88) and CKD stage 4-5 (aOR 15.76; 95% CI: 3.22-77.28). Other predictors of IMD were diagnosis of diabetes mellitus (aOR 6.40; 95% CI: 2.15-19.01), number of prescribed medications of 5 or more (aOR 4.69; 95% CI: 1.55-14.20), and eGFR reduction of more than 25% over one year (aOR 2.82; 95% CI: 1.41-5.65). Within the limitations of this study, we conclude that the occurrence of IMD for CVD prevention was low in CKD patients in this primary care clinic. Medications with inappropriate dosages identified in this study include simvastatin, fenofibrate, hydrochlorothiazide, spironolactone, metformin, gliclazide, sitagliptin, dapagliflozin and empagliflozin. Clinicians should consider the predictors of inappropriate medication dosages listed above when prescribing to patients with CKD to reduce the risk of medications-related toxicities and adverse effects. Limitations of this study should be considered when interpreting the findings presented.
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Affiliation(s)
| | - Mohamed-Syarif Mohamed-Yassin
- Department of Primary Care Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia
| | | | | | - Mohamad Ya'akob Yusof
- Department of Primary Care Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia
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Li Y, He X, Li Z, Li D, Yuan X, Yang J. Construction and dual internal validation of a short-term prognostic scoring tool for sepsis. Heliyon 2023; 9:e14941. [PMID: 37025776 PMCID: PMC10070133 DOI: 10.1016/j.heliyon.2023.e14941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 03/15/2023] [Accepted: 03/22/2023] [Indexed: 03/30/2023] Open
Abstract
Background To construct and validate a simple and easily administered scoring tool for the prediction of short-term prognostic survival in adult patients with sepsis. Methods This study is a retrospective and prospective cohort study. A total of 382 patients with sepsis. 274 sepsis patients from January 2020 to December 2020 were collected as the modeling group and 54 sepsis patients from January 2021 to December 2021 and April to May 2022 in the hospital were randomly collected as the validation group. They were divided into survival and non-survival groups according to the outcome. The receiver operating characteristic (ROC) curves were plotted with subgroup analysis. The resulting models were tested using the Hosmer-Lemeshow test. The prognostic value of the variables on prognosis was expressed using the area under the receiver operating characteristic curve (AUC). A scoring tool was constructed and tested for the prognostic value of this score in the validation group. Results The model had an AUC of 0.880 [95% CI (0.838-0.922), P < 0.001], model sensitivity of 81.15%, and specificity of 80.26% for predicting short-term prognosis in patients with sepsis. Further simplifying the model scoring rules and adding the lactate variable, the AUCs was 0.876 [95% CI (0.833-0.918)], P < 0.001], sensitivity was 78.69%, specificity was 82.89%, and scoring criteria were established. the AUCs of the internally validated model in 2021 and 2022 were 0.968 [95% CI (0.916 to 1.000), P < 0.001] and 0.943 [95% CI (0.873 to 1.000), P < 0.001], indicating that the constructed scoring tool has a good predictive value for short-term survival outcomes in patients with sepsis. Conclusions Age, shock, lactate, lactate/albumin ratio (L/A), and interleukin-6 (IL-6) are five risk factors for adult sepsis prognosis in an early emergency. This scoring tool is developed to quickly assess the short-term survival outcome in adult sepsis patients. It is straightforward and easy to administer. It also has a high prognostic predictive value.The Chinese Clinical Trial Registry (ChiCTR2200058375).
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Mahboob A, Senevirathne DKL, Paul P, Nabi F, Khan RH, Chaari A. An investigation into the potential action of polyphenols against human Islet Amyloid Polypeptide aggregation in type 2 diabetes. Int J Biol Macromol 2023; 225:318-350. [PMID: 36400215 DOI: 10.1016/j.ijbiomac.2022.11.038] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/24/2022] [Accepted: 11/04/2022] [Indexed: 11/17/2022]
Abstract
Type 2 diabetes (T2D), a chronic metabolic disease characterized by hyperglycemia, results in significant disease burden and financial costs globally. Whilst the majority of T2D cases seem to have a genetic basis, non-genetic modifiable and non-modifiable risk factors for T2D include obesity, diet, physical activity and lifestyle, smoking, age, ethnicity, and mental stress. In healthy individuals, insulin secretion from pancreatic islet β-cells is responsible for keeping blood glucose levels within normal ranges. T2D patients suffer from multifactorial onset of β-cell dysfunction and/or loss of β-cell mass owing to reactive oxygen species (ROS) production, mitochondrial dysfunction, autophagy, and endoplasmic reticulum (ER) stress. Most predominantly however, and the focus of this review, it is the aggregation and misfolding of human Islet Amyloid Polypeptide (hIAPP, also known as amylin), which is detrimental to β-cell function and health. Whilst hIAPP is found in healthy individuals, its misfolded version is cytotoxic and able to induce β-cell dysfunction and/or death through various mechanisms including membrane changes in β-cell causing influx of calcium ions, arresting complete granule membrane recovery and ER stress. There are several existing therapeutics for T2D. However, there is a need for alternative or adjunct therapies for T2D with milder adverse effects and greater availability. Foremost among the potential natural therapeutics are polyphenols. Extensive data from studies evaluating the potential of polyphenols to inhibit hIAPP aggregation and disassemble aggregated hIAPP are promising. Moreover, in-vivo, and in-silico studies also highlight the potential effects of polyphenols against hIAPP aggregation and mitigation of larger pathological effects of T2D. Whilst there have been some promising clinical studies on the therapeutic potential of polyphenols, extensive further clinical studies and in-vitro studies evaluating the mechanisms of action and ideal doses for many of these compounds are required. The need for these studies is made more important by the postulated link between Alzheimer's disease (AD) and T2D pathophysiology given the similar aggregation process of their respective amyloid proteins, which evokes thoughts of cross-reactive polyphenols which can be effective for both AD and T2D patients.
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Affiliation(s)
- Anns Mahboob
- Premedical Division Weill Cornell Medicine Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar
| | | | - Pradipta Paul
- Weill Cornell Medicine Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar
| | - Faisal Nabi
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202001, India
| | - Rizwan Hasan Khan
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202001, India
| | - Ali Chaari
- Premedical Division Weill Cornell Medicine Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar.
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Plaz Torres MC, Jaffe A, Perry R, Marabotto E, Strazzabosco M, Giannini EG. Diabetes medications and risk of HCC. Hepatology 2022; 76:1880-1897. [PMID: 35239194 PMCID: PMC9790535 DOI: 10.1002/hep.32439] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/23/2022] [Accepted: 02/24/2022] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes mellitus is a recognized risk factor for HCC in patients with liver disease, independent from the etiology of their liver disease. Hence, prevention and treatment of type 2 diabetes mellitus and its underlying cause, insulin resistance, should be considered a treatment target for patients with liver disease. The drug armamentarium for diabetes is wide and consists of agents with insulin-sensitizing activity, agents that stimulate insulin secretion, insulin itself, and agents that reduce gastrointestinal and urinary glucose absorption. From an endocrinology perspective, the main goal of treatment is the achievement of euglycemia; however, in patients at risk of, or with known underlying liver disease, the choice of diabetic medication as it relates to potential hepatic carcinogenesis remains complex and should be carefully considered. In the last decade, increasing evidence has suggested that metformin may reduce the risk of HCC, whereas evidence for other classes of diabetic medications, particularly some of the newer agents including the sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, is fewer and often inconsistent. In this review, we aim to summarize the current evidence on the potential effects of the most widely used diabetic agents on liver cancer tumorigenesis.
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Affiliation(s)
- Maria Corina Plaz Torres
- Gastroenterology Unit, Department of Internal MedicineIRCCS—Ospedale Policlinico San Martino, University of GenoaGenoaItaly
| | - Ariel Jaffe
- Liver CenterDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
| | - Rachel Perry
- Liver CenterDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
- Section of EndocrinologyDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
- Department of Cellular and Molecular PhysiologyYale University School of MedicineNew HavenConnecticutUSA
| | - Elisa Marabotto
- Gastroenterology Unit, Department of Internal MedicineIRCCS—Ospedale Policlinico San Martino, University of GenoaGenoaItaly
| | - Mario Strazzabosco
- Liver CenterDepartment of Internal MedicineYale University School of MedicineNew HavenConnecticutUSA
| | - Edoardo G. Giannini
- Gastroenterology Unit, Department of Internal MedicineIRCCS—Ospedale Policlinico San Martino, University of GenoaGenoaItaly
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Brand KMG, Schlachter J, Foch C, Boutmy E. Quality and Characteristics of 4241 Case Reports of Lactic Acidosis in Metformin Users Reported to a Large Pharmacovigilance Database. Ther Clin Risk Manag 2022; 18:1037-1047. [PMID: 36389204 PMCID: PMC9642855 DOI: 10.2147/tcrm.s372430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 07/11/2022] [Indexed: 11/05/2022] Open
Abstract
Objective Metformin-associated lactic acidosis (MaLA) occurs rarely and is thus difficult to study. We analysed 4241 individual case safety reports of lactic acidosis (LA) that implicated metformin as a suspected drug reported to the pharmacovigilance database of Merck KGaA, Darmstadt, Germany. The primary objective was to review reports for quality and completeness of data to support diagnoses of MaLA. We also explored the correlations between reported biomarkers, and associations between biomarkers and outcomes. Research Design and Methods Records were analysed for completeness in supporting diagnoses of LA or metformin-associated LA (MaLA), against commonly used diagnostic criteria. Correlations between indices of exposure to metformin and biomarkers of LA and mortality were investigated. Results Missing data was common, especially for plasma metformin. Clinical/biomarker evidence supported a diagnosis of LA in only 33% of cases (LA subpopulation) and of MaLA in only 9% (MaLA subpopulation). The metformin plasma level correlated weakly with plasma lactate (positive) and pH (negative). About one-fifth (21.9%) of cases reported a fatal outcome. Metformin exposure (plasma level or dose) was not associated with increased mortality risk (there was a suggestion of decreased risk at higher levels of exposure to metformin). Plasma lactate was the only variable associated with increased risk of mortality. Examination of concomitant risk factors for MaLA identified renal dysfunction (including of iatrogenic origin) as a potential driver of mortality in this population. Conclusion Despite the high frequency of missing data, this is the largest analysis of cases of MaLA supported by measurements of circulating metformin, and lactate, and pH, to date. Plasma lactate, and not metformin dose or plasma level, appeared to be the main driver of mortality in the setting of LA or MaLA. Further research with more complete case reports is required.
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Affiliation(s)
- Kerstin M G Brand
- Global Medical Affairs, Merck Healthcare KGaA, Darmstadt, Germany
- Correspondence: Kerstin MG Brand, Global Medical Affairs, Merck Healthcare KGaA, F135/00_N1, Frankfurter Str. 250, Darmstadt, 64293, Germany, Tel +49 6151 72 2301, Email
| | | | - Caroline Foch
- Global Epidemiology, Merck Healthcare KGaA, Darmstadt, Germany
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13
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Chen CC, Ko Y, Chen CH, Hung YJ, Wei TE, Chang TH, Ke SS, Kuo KN, Chen C. Relationship between metformin use and lactic acidosis in advanced chronic kidney disease: The REMIND-TMU study. Am J Med Sci 2022; 364:575-582. [PMID: 35483434 DOI: 10.1016/j.amjms.2022.01.026] [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: 02/04/2021] [Revised: 10/03/2021] [Accepted: 01/20/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND Evidence of metformin-associated lactic acidosis (MALA) in advanced chronic kidney disease (CKD) has been limited due to high mortality rate but rare incidence rate. The mechanism of increased MALA in advanced CKD is mainly based on the hypothesis of decreased drug elimination, which might also be confounded by increased comorbidities as CKD progresses. The goal of the study is to analyze the incidence and associated factors of lactic acidosis between metformin user and non-user with advanced CKD. METHODS This study used a three million population-based, propensity score-matched cohort from 2008 to 2016. The primary outcome was laboratory-defined lactic acidosis. Relationships between the probability of lactic acidosis and various estimated glomerular filtration rate (eGFR) values in advanced CKD patients were also presented in regression analysis. RESULTS Adults with type 2 diabetes whose eGFR was <30 mL/min/1.73 m2 were enrolled in this study. After the process of propensity score matching, 7707 patients were divided into metformin and non-metformin groups. In linear regression model, metformin significantly increased the risk of lactic acidosis (p=0.0204) as the eGFR declined in advanced CKD over a mean follow up of over 600 days even after confounder adjustment with age, sex and comorbidities. CONCLUSIONS Metformin was associated with a significant increased risk of laboratory-defined lactic acidosis (p=0.0204) even after adjusting confounder such as age, sex and underlying comorbidities. This "REMIND" study reminds us that metformin-associated lactic acidosis is mainly caused by decreased drug renal elimination other than underlying comorbidities in advanced CKD patients.
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Affiliation(s)
- Chien-Chou Chen
- Division of Nephrology, Department of Internal Medicine, Tri-service General Hospital Songshan Branch, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yu Ko
- Department of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Research Center for Pharmacoeconomics, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Chin-Hua Chen
- Biostatistics Center and School of Health Care Administration, College of Management, Taipei Medical University, Taipei, Taiwan
| | - Yi-Jen Hung
- Division of Endocrinology and Metabolism, Tri-Service General Hospital, Taipei, Taiwan
| | - Ting-En Wei
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, Tri-service General Hospital Songshan Branch, Taipei, Taiwan
| | - Tzu-Hao Chang
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Clinical Big Data Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Sih-Shan Ke
- Department of Public Health, School of Medicine, College of Medicine, Cochrane Taiwan, Taipei Medical University, Taipei, Taiwan
| | - Ken N Kuo
- Cochrane Taiwan, Taipei Medical University, Taipei, Taiwan
| | - Chiehfeng Chen
- Department of Public Health, School of Medicine, College of Medicine, Cochrane Taiwan, Taipei Medical University, Taipei, Taiwan; Cochrane Taiwan, Taipei Medical University, Taipei, Taiwan; Division of Plastic Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Evidence-based Medicine Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
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14
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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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15
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The influence of metformin transporter gene SLC22A1 and SLC47A1 variants on steady-state pharmacokinetics and glycemic response. PLoS One 2022; 17:e0271410. [PMID: 35905099 PMCID: PMC9337647 DOI: 10.1371/journal.pone.0271410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 06/29/2022] [Indexed: 11/19/2022] Open
Abstract
Interindividual variation is important in the response to metformin as the first-line therapy for type-2 diabetes mellitus (T2DM). Considering that OCT1 and MATE1 transporters determine the metformin pharmacokinetics, this study aimed to investigate the influence of SLC22A1 and SLC47A1 variants on the steady-state pharmacokinetics of metformin and the glycemic response. This research used the prospective-cohort study design for 81 patients with T2DM who received 500 mg metformin twice a day from six primary healthcare centers. SLC22A1 rs628031 A>G (Met408Val) and Met420del genetic variants in OCT1 as well as SLC47A1 rs2289669 G>A genetic variant in MATE1 were examined through the PCR-RFLP method. The bioanalysis of plasma metformin was performed in the validated reversed-phase HPLC-UV detector. The metformin steady-state concentration was measured for the trough concentration (Cssmin) and peak concentration (Cssmax). The pharmacodynamic parameters of metformin use were the fasting blood glucose (FBG) and glycated albumin (GA). Only SLC22A1 Met420del alongside estimated-glomerular filtration rate (eGFR) affected both Cssmax and Cssmin with an extremely weak correlation. Meanwhile, SLC47A1 rs2289669 and FBG were correlated. This study also found that there was no correlation between the three SNPs studied and GA, so only eGFR and Cssmax influenced GA. The average Cssmax in patients with the G allele of SLC22A1 Met408Val, reaching 1.35-fold higher than those with the A allele, requires further studies with regard to metformin safe dose in order to avoid exceeding the recommended therapeutic range.
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16
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Qureshi R, Nasir K, Dhrolia M, Ahmad A. A Comparative Study of Acidosis in Diabetic Advanced Chronic Kidney Disease Patients on and off Metformin. Cureus 2022; 14:e21291. [PMID: 35186553 PMCID: PMC8846262 DOI: 10.7759/cureus.21291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2022] [Indexed: 11/29/2022] Open
Abstract
Aim The aim of the study is to assess the risk of acidosis in diabetic advanced chronic kidney disease (CKD) patients on and off metformin. Methods This retrospective descriptive study was conducted in the nephrology department in The Kidney Centre Post Graduate Training Institute (TKC PGTI) Karachi from February to April 2020. We reviewed the records of all patients over 18 years old who visited the nephrology outpatient department in three months in 2020 (from February 2020 to April 2020), who had CKD (stage 2-5), are not on dialysis, and had type 2 diabetes. These were divided into two groups: those on metformin for more than one year and those not on metformin. We looked at hospitalizations due to acidosis in the previous one-year period. Results A total of 524 CKD patients had diabetes; out of those, 268 patients were on metformin, and 256 were not on metformin. The male vs. female distribution was 52.1% vs. 47.9%. A total of 114 (21.8%) patients required admission in the previous one-year period, and only 12 hospitalized patients had acidosis, seven (58.3%) were on metformin, and five (41.7%) were not on metformin, which was statistically insignificant. Conclusion Biguanides, especially metformin, is a known oral hypoglycemic drug used for decades to treat type 2 diabetes mellitus (DM). Metformin use is related to a rare but serious adverse event, metformin-associated lactic acidosis (MALA), especially in renal failure patients. In our study, metformin use in CKD diabetic patients did not result in more admissions due to acidosis than non-metformin users.
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Alhassani RY, Bagadood RM, Balubaid RN, Barno HI, Alahmadi MO, Ayoub NA. Drug Therapies Affecting Renal Function: An Overview. Cureus 2021; 13:e19924. [PMID: 34976524 PMCID: PMC8712249 DOI: 10.7759/cureus.19924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/26/2021] [Indexed: 11/24/2022] Open
Abstract
Undesirable side effects of medication are inevitable. Due to the role of the kidneys in clearance and filtration, the renal system faces a unique situation when it comes to the side effects of drugs. It has an important role for different classes of drugs to be excreted, and drugs are a key factor for this system to be at risk. Medications in articles were divided into classes using the standard set by the Saudi Pharmaceutical Journal. Many drug classes cause renal insults. The top six classes were pain killers, antibiotics, proton pump inhibitors, antidiabetics, antihyperlipidemics, and agents for erectile dysfunction. Renal insults caused by these agents could vary in severity. Some drugs could cause nephrotoxicity from one dose, while others may only need continuous monitoring. Different populations also operate under different rules, as some people need dose adjustments while others who are medically free of major illnesses do not. A variety of unfavorable outcomes for the kidney could take place, such as acute kidney injury, chronic kidney disease, and end-stage renal disease, and unfortunately, some of these issues could lead to the need for renal replacement therapies. The outcome of this review paper will help multidisciplinary physicians to understand the renal side effects of the most used drug classes in the Kingdom of Saudi Arabia, their destructive mechanisms, and most importantly, the clinical presentations of renal dysfunction in relation to each class. Emphasizing these adverse effects will prevent future unfavorable outcomes, especially in commonly used drugs that are frequently prescribed for different age groups. Moreover, some of these drugs are considered to be over-the-counter medications, which makes them a serious problem that needs to be handled cautiously.
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Koons A, Amaducci AM, Katz KD. Reversible Total Vision Loss Caused by Severe Metformin-associated Lactic Acidosis: A Case Report. Clin Pract Cases Emerg Med 2021; 5:206-209. [PMID: 34437006 PMCID: PMC8143825 DOI: 10.5811/cpcem.2021.3.51141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/05/2021] [Indexed: 11/25/2022] Open
Abstract
Introduction Metformin is a biguanide used to treat diabetes mellitus (DM). Metformin-associated lactic acidosis (MALA) carries a high mortality and can occur in patients with renal failure from drug bioaccumulation. Reversible vision loss is a highly unusual, rarely reported complication of MALA. We present a case of a patient whose serum metformin concentration was unusually high and associated with vision loss. Case Report A 60-year-old woman presented to an outside hospital emergency department with acute vision loss after being found at home confused, somnolent, and hypoglycemic, having last being seen normal two days prior. She reported vomiting and diarrhea during that time and a recently treated urinary tract infection. The visual loss resolved with continuous renal replacement therapy. Conclusion This novel case of a patient with Type II DM prescribed metformin and insulin who developed reversible vision loss while suffering from MALA highlights the potential for vision loss in association with MALA.
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Affiliation(s)
- Andrew Koons
- Lehigh Valley Health Network, Department of Emergency and Hospital Medicine, Allentown, Pennsylvania
| | - Alexandra M Amaducci
- Lehigh Valley Health Network, Department of Emergency and Hospital Medicine, Allentown, Pennsylvania
| | - Kenneth D Katz
- Lehigh Valley Health Network, Department of Emergency and Hospital Medicine, Allentown, Pennsylvania
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19
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Yang A, Shi M, Wu H, Lau ESH, Ma RCW, Kong APS, So WY, Luk AOY, Chan JCN, Chow E. Long-term metformin use and risk of pneumonia and related death in type 2 diabetes: a registry-based cohort study. Diabetologia 2021; 64:1760-1765. [PMID: 33844069 DOI: 10.1007/s00125-021-05452-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 02/12/2021] [Indexed: 02/06/2023]
Abstract
AIMS/HYPOTHESIS The long-term effects of metformin in individuals with type 2 diabetes who are at increased risk of severe respiratory infections are unknown. This study aimed to evaluate the effects of metformin use on the risk of first pneumonia hospitalisation and pneumonia-related death in a cohort of Chinese individuals with type 2 diabetes. METHODS We performed a retrospective analysis of a consecutive cohort of 22,638 individuals with type 2 diabetes in the Hong Kong Diabetes Register enrolled between 2001 and 2018, with follow-up until 31 December 2019. Overlap propensity-score weighting was performed to balance baseline characteristics. RESULTS Of 22,638 individuals with type 2 diabetes, after excluding those who had not been prescribed any glucose-lowering drugs (GLDs) and/or with eGFR ≤30 ml min-1 [1.73 m]-2 or treated by dialysis and/or treated with insulin at baseline, we identified 15,784 either prevalent or incident metformin users and 917 users of other GLDs during a mean follow-up period of 7.5 years. Overlap-weighted analysis showed an HR of 0.63 (95% CI 0.52, 0.77) for first pneumonia hospitalisation and 0.49 (95% CI 0.33, 0.73) for pneumonia-related death in metformin users vs users of other GLDs; similar observations resulted following stratification by sex and kidney function. There was also a negative association between metformin exposure over time (proportion of duration of metformin prescriptions during the total follow-up time) and pneumonia events using the penalised spline analysis. Metformin users had a lower neutrophil/lymphocyte ratio at first pneumonia hospitalisation vs non-metformin users (mean [95% CI]: 12.8 [12.1, 13.5] vs 14.8 [12.3, 17.3], p = 0.032). The rate of metformin-associated lactic acidosis was 2.5 per 100,000 person-years. The lower risk of pneumonia events was also observed among incident metformin users vs other GLD users. CONCLUSIONS/INTERPRETATION Long-term use of metformin was associated with reduced risk of pneumonia and pneumonia-related death among Chinese individuals with diabetes. The relevance of these results to other respiratory infections merits further investigation.
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Affiliation(s)
- Aimin Yang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
| | - Mai Shi
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
| | - Hongjiang Wu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
| | - Eric S H Lau
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
| | - Ronald C W Ma
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
| | - Alice P S Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
| | - Wing Yee So
- Hong Kong Hospital Authority Head Office, Kowloon, Hong Kong Special Administrative Region, China
| | - Andrea O Y Luk
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
| | - Juliana C N Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China
| | - Elaine Chow
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China.
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China.
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20
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Bahat G, Catikkas NM, Karan MA, Petrovic M. Management of type 2 diabetes mellitus in older adults: eight case studies with focus SGLT-2 inhibitors and metformin. Acta Clin Belg 2021; 77:727-734. [PMID: 34251983 DOI: 10.1080/17843286.2021.1952379] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Objectives: Sodium-glucose co-transporter-2 (SGLT-2) inhibitors have been recently introduced for type 2 diabetes treatment with significant cardiovascular, renal benefits. Yet, they have frequently been refrained in older adults. Metformin is regarded the first-line diabetes therapy for all ages; still it is associated with weight loss and frailty in older adults. We aimed to outline our experience with three oldest-old patients with high cardiovascular risk managed with SGLT-2 inhibitors, and five patients with anorexia/weight loss managed by metformin cessation. Methods: We outlined demographics, comorbidities, geriatric syndromes, functional status, and diabetes duration, and presented the changes in frailty by noting pre-intervention and post-intervention frailty scores. We outlined benefits and side effects related to SGLT-2 inhibitors, and the deprescription reasons and represcription practices of metformin therapy. We gave details on baseline and current diabetes treatment, overall medication regimen, and current status of the patients. Results: Among the case studies with SGLT-2 inhibitors, two patients were frail and reversed to pre-frailty status after SGLT-2 intervention, while the third patient was and remained robust. All patients had clinical improvements with better blood pressure and glucose control. Among the case studies treated with metformin, all were frail before the cessation of metformin. Four reversed to pre-frailty and one became robust after intervention. Conclusion: The findings of our case studies suggest considering SGLT-2 inhibitors in patients with accompanying heart failure/high cardiovascular risk factors and cessation of metformin in those with malnutrition/malnutrition risk. These approaches have potential to improve frailty and inappropriate medication use in diabetic older adults.
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Affiliation(s)
- Gulistan Bahat
- Department of Internal Medicine, Division of Geriatrics, Istanbul University, Istanbul Medical School, Istanbul, Turkey
| | - Nezahat Muge Catikkas
- Department of Internal Medicine, Division of Geriatrics, Istanbul University, Istanbul Medical School, Istanbul, Turkey
| | - Mehmet Akif Karan
- Department of Internal Medicine, Division of Geriatrics, Istanbul University, Istanbul Medical School, Istanbul, Turkey
| | - Mirko Petrovic
- Department of Internal Medicine and Paediatrics, Section of Geriatrics, Ghent University, Ghent, Belgium
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21
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Bjällmark A, Bazzi M, Karlsson M, Krakys E, Kihlberg J. Radiology departmental policy compliance with Swedish guidelines regarding post-contrast acute kidney injury for examinations with iodinated contrast media. Radiography (Lond) 2021; 27:1058-1063. [PMID: 34023227 DOI: 10.1016/j.radi.2021.04.009] [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: 12/16/2020] [Revised: 04/16/2021] [Accepted: 04/20/2021] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Guidelines concerning intravenous iodinated contrast media (CM) during computed tomography (CT) examinations are important to follow to minimize the risk for post-contrast acute kidney injury (PC-AKI). The purpose of this study was to investigate the radiology departmental policy compliance with Swedish guidelines concerning PC-AKI. METHODS In February 2020, an electronic survey was distributed to the responsible radiographer at 41 radiology departments in all university hospitals and medium-sized hospitals in Sweden. The questions focused on routines around renal functional tests, individualized contrast administration and handling of patients with diabetes mellitus taking metformin. RESULTS The response rate was 83%. Seventy-six percent (n = 26) of radiology departments calculated estimated glomerular filtration rate (eGFR) from serum creatinine prior to CM administration, but only 24% (n = 8) followed the recommendation to calculate eGFR from both serum creatinine and cystatin C. For acute/inpatients, 55% (n = 18) followed the recommendation that renal functional tests should be performed within 12 h before CM administration. For elective patients, 97% (n = 33) followed the recommendation to have eGFR newer than three months which is acceptable for patients with no history of disease that may have affected renal function. Approximately 80% of the radiology departments followed the recommendation that CM dose always should be individually adjusted to patient eGFR. Seventy-six percent (n = 26) followed the recommendation to continue with metformin at eGFR ≥ 45 ml/min. CONCLUSION Compliance with the national guidelines was high regarding routines around renal functional tests, dose adjustment of CM and metformin discontinuation. Improvements can be made in using both cystatin C and serum creatinine for eGFR calculations as well as ensuring renal function tests within 12 h for acute/inpatients with acute disease that may affect renal function. IMPLICATIONS FOR PRACTICE This study raises awareness of the importance of adhering to guidelines in healthcare. To have knowledge about the current level of compliance regarding PCI-AKI is important to maintain and develop effective clinical implementation of guidelines. The variation in practice seen in this study emphasizes the need of more effective implementation strategies to ensure adherence with best practice.
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Affiliation(s)
- A Bjällmark
- Department of Natural Science and Biomedicine, School of Health and Welfare, Jönköping University, Jönköping, Sweden.
| | - M Bazzi
- Department of Natural Science and Biomedicine, School of Health and Welfare, Jönköping University, Jönköping, Sweden
| | - M Karlsson
- Department of Radiology, Höglandssjukhuset, Eksjö, Sweden
| | - E Krakys
- Department of Radiology, Motala Hospital, Motala, Sweden
| | - J Kihlberg
- Department of Radiology in Linköping, and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden; Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden
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22
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Kathuria D, Raul AD, Wanjari P, Bharatam PV. Biguanides: Species with versatile therapeutic applications. Eur J Med Chem 2021; 219:113378. [PMID: 33857729 DOI: 10.1016/j.ejmech.2021.113378] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 03/04/2021] [Accepted: 03/08/2021] [Indexed: 12/18/2022]
Abstract
Biguanides are compounds in which two guanidine moieties are fused to form a highly conjugated system. Biguanides are highly basic and hence they are available as salts mostly hydrochloride salts, these cationic species have been found to exhibit many therapeutic properties. This review covers the research and development carried out on biguanides and accounts the various therapeutic applications of drugs containing biguanide group-such as antimalarial, antidiabetic, antiviral, anticancer, antibacterial, antifungal, anti-tubercular, antifilarial, anti-HIV, as well as other biological activities. The aim of this review is to compile all the medicinal chemistry applications of this class of compounds so as to pave way for the accelerated efforts in finding the drug action mechanisms associated with this class of compounds. Importance has been given to the organic chemistry of these biguanide derivatives also.
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Affiliation(s)
- Deepika Kathuria
- University Center for Research and Development, Chandigarh University, Gharuan, Punjab, 140413, India
| | - Akshay D Raul
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India
| | - Pravin Wanjari
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India
| | - Prasad V Bharatam
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India.
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23
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Tan FCJH, Ang SB, Bee YM. Metformin use in patients with type 2 diabetes mellitus and chronic kidney disease: An evidence-based review. ANNALS OF THE ACADEMY OF MEDICINE, SINGAPORE 2021. [PMID: 33733259 DOI: 10.47102/annals-acadmedsg.2020464] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
INTRODUCTION Practice guidelines advise caution on the use of metformin in patients with type 2 diabetes mellitus with chronic kidney disease (CKD). This review aims to examine the evidence for the benefits and risks of metformin use in patients with T2DM and CKD. METHODS The Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials and PubMed were searched; the references of selected papers were hand searched. Systematic reviews, randomised controlled trials, cohort studies, case series and case-control studies were included. The full text of selected articles was reviewed. The outcomes studied were all-cause mortality, cardiovascular complications, lactic acidosis and worsening of renal function. Recommendations were graded according to the Scottish Intercollegiate Guidelines Network system. RESULTS A total of 139 unique articles were identified, 14 of which met the inclusion criteria and were selected for full-text review. Four cohort studies reported an association between metformin use and improved all-cause mortality in CKD stage 4 and better. Two cohort studies reported improved cardiovascular outcomes with metformin use. Four cohort studies, 1 case series and 1 case-control study reported no significant association between metformin use and an increased risk of lactic acidosis in CKD. There is a moderate level of evidence to support reduced mortality, improved cardiovascular outcomes and a low risk of lactic acidosis with metformin use in patients with T2DM and with CKD stage 4 and above. CONCLUSION Existing recommendations to restrict metformin use in diabetes patients with CKD need to be reviewed in light of emerging evidence supporting its overall benefits in these patients.
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24
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Alvarez CA, Halm EA, Pugh MJV, McGuire DK, Hennessy S, Miller RT, Lingvay I, Vouri SM, Zullo AR, Yang H, Chansard M, Mortensen EM. Lactic acidosis incidence with metformin in patients with type 2 diabetes and chronic kidney disease: A retrospective nested case-control study. Endocrinol Diabetes Metab 2021; 4:e00170. [PMID: 33532612 PMCID: PMC7831229 DOI: 10.1002/edm2.170] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 05/28/2020] [Accepted: 06/27/2020] [Indexed: 12/12/2022] Open
Abstract
Objective Compare rates of lactic acidosis (LA) among metformin-exposed and unexposed patients with type 2 diabetes mellitus and varying degrees of chronic kidney disease (CKD). Research Design and Methods Retrospective, nested case-control study using data from national VA Corporate Data Warehouse. All adult patients with type 2 diabetes and CKD newly dispensed any antihyperglycaemic medication during FY 2003-13 were included. The outcome was LA hospitalization or serum lactate >5 mEq/L. Exposure to metformin was evaluated in the three months prior to event. Estimates were adjusted for 31 covariates, including demographics, comorbidities and medications. Results Overall, 320 882 patients were included, contributing a total of 1 331 784 person-years of follow-up. LA occurred in 2 665 patients, generating an overall incidence rate of 2.00 (95% CI 1.93-2.08) per 1000 person-years. Metformin exposure in the prior 3 months was associated with an elevated adjusted hazard of LA (HR 1.97, 95% CI 1.69-2.29). No association was evident in patients with CKD stage 1 or 2 (HR 1.05, 95% CI 0.71-1.57), but associations were present and progressively greater in patients with CKD stage 3a through 5: HR 3.09, 95% CI 2.19-4.35 in CKD 3a, HR 3.34, 95% CI 1.95-5.72 in CKD 3b, HR 7.87, 95% CI 3.51-17.61 in CKD stage 4&5. Conclusion Metformin was not associated with an elevated risk of LA in persons with stage 1-2 CKD, but was associated with a progressively higher risk at more advanced stages of CKD.
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Affiliation(s)
- Carlos A. Alvarez
- Texas Tech University Health Sciences CenterSchool of PharmacyDallasTXUSA
- University of Texas Southwestern Medical CenterDallasTXUSA
- Veterans Affairs North Texas Health Care SystemDallasTXUSA
| | - Ethan A. Halm
- University of Texas Southwestern Medical CenterDallasTXUSA
| | | | | | - Sean Hennessy
- University of Pennsylvania Perelman School of MedicinePhiladelphiaPAUSA
| | - Richard T. Miller
- University of Texas Southwestern Medical CenterDallasTXUSA
- Veterans Affairs North Texas Health Care SystemDallasTXUSA
| | - Ildiko Lingvay
- University of Texas Southwestern Medical CenterDallasTXUSA
| | - Scott M. Vouri
- University of Florida College of PharmacyGainesvilleFLUSA
| | - Andrew R. Zullo
- Brown University School of Public Health and Providence Veterans Affairs Medical CenterProvidenceRIUSA
| | - Hui Yang
- Texas Tech University Health Sciences CenterSchool of PharmacyDallasTXUSA
| | - Matt Chansard
- University of Texas Southwestern Medical CenterDallasTXUSA
| | - Eric M. Mortensen
- University of Texas Southwestern Medical CenterDallasTXUSA
- Veterans Affairs North Texas Health Care SystemDallasTXUSA
- University of Connecticut School of MedicineFarmingtonCTUSA
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25
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Ahmad E, Sargeant JA, Zaccardi F, Khunti K, Webb DR, Davies MJ. Where Does Metformin Stand in Modern Day Management of Type 2 Diabetes? Pharmaceuticals (Basel) 2020; 13:E427. [PMID: 33261058 PMCID: PMC7761522 DOI: 10.3390/ph13120427] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/24/2020] [Accepted: 11/25/2020] [Indexed: 02/06/2023] Open
Abstract
Metformin is the most commonly used glucose-lowering therapy (GLT) worldwide and remains the first-line therapy for newly diagnosed individuals with type 2 diabetes (T2D) in management algorithms and guidelines after the UK Prospective Diabetes Study (UKPDS) showed cardiovascular mortality benefits in the overweight population using metformin. However, the improved Major Adverse Cardiovascular Events (MACE) realised in some of the recent large cardiovascular outcomes trials (CVOTs) using sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have challenged metformin's position as a first-line agent in the management of T2D. Many experts now advocate revising the existing treatment algorithms to target atherosclerotic cardiovascular disease (ASCVD) and improving glycaemic control as a secondary aim. In this review article, we will revisit the major cardiovascular outcome data for metformin and include a critique of the UKPDS data. We then review additional factors that might be pertinent to metformin's status as a first-line agent and finally answer key questions when considering metformin's role in the modern-day management of T2D.
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Affiliation(s)
- Ehtasham Ahmad
- Diabetes Research Centre, University of Leicester, Leicester LE5 4PW, UK; (J.A.S.); (F.Z.); (K.K.); (D.R.W.); (M.J.D.)
- NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and the University of Leicester, Leicester LE5 4PW, UK
| | - Jack A. Sargeant
- Diabetes Research Centre, University of Leicester, Leicester LE5 4PW, UK; (J.A.S.); (F.Z.); (K.K.); (D.R.W.); (M.J.D.)
- NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and the University of Leicester, Leicester LE5 4PW, UK
| | - Francesco Zaccardi
- Diabetes Research Centre, University of Leicester, Leicester LE5 4PW, UK; (J.A.S.); (F.Z.); (K.K.); (D.R.W.); (M.J.D.)
- NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and the University of Leicester, Leicester LE5 4PW, UK
| | - Kamlesh Khunti
- Diabetes Research Centre, University of Leicester, Leicester LE5 4PW, UK; (J.A.S.); (F.Z.); (K.K.); (D.R.W.); (M.J.D.)
- NIHR Applied Research Collaborations (ARC), East Midlands, Leicester LE5 4PW, UK
| | - David R. Webb
- Diabetes Research Centre, University of Leicester, Leicester LE5 4PW, UK; (J.A.S.); (F.Z.); (K.K.); (D.R.W.); (M.J.D.)
- NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and the University of Leicester, Leicester LE5 4PW, UK
| | - Melanie J. Davies
- Diabetes Research Centre, University of Leicester, Leicester LE5 4PW, UK; (J.A.S.); (F.Z.); (K.K.); (D.R.W.); (M.J.D.)
- NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and the University of Leicester, Leicester LE5 4PW, UK
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26
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Hanna RM, Rhee CM, Kalantar-Zadeh K. Metformin in chronic kidney disease: a strong dose of caution. Kidney Int 2020; 98:1101-1105. [PMID: 33126975 DOI: 10.1016/j.kint.2020.04.060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/19/2020] [Accepted: 04/22/2020] [Indexed: 10/23/2022]
Affiliation(s)
- Ramy M Hanna
- Department of Medicine, Division of Nephrology, University of California Irvine Medical Center, Irvine, California, USA; Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology, Hypertension and Kidney Transplantation, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA
| | - Connie M Rhee
- Department of Medicine, Division of Nephrology, University of California Irvine Medical Center, Irvine, California, USA; Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology, Hypertension and Kidney Transplantation, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Nephrology Section, Department of Medicine, Veterans Affairs Long Beach Healthcare System, Long Beach, California, USA
| | - Kamyar Kalantar-Zadeh
- Department of Medicine, Division of Nephrology, University of California Irvine Medical Center, Irvine, California, USA; Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology, Hypertension and Kidney Transplantation, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA; Nephrology Section, Department of Medicine, Veterans Affairs Long Beach Healthcare System, Long Beach, California, USA; Lundquist Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
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27
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Chung W, Promrat K, Wands J. Clinical implications, diagnosis, and management of diabetes in patients with chronic liver diseases. World J Hepatol 2020; 12:533-557. [PMID: 33033564 PMCID: PMC7522556 DOI: 10.4254/wjh.v12.i9.533] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/03/2020] [Accepted: 08/15/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus (DM) negatively affects the development and progression of chronic liver diseases (CLD) of various etiologies. Concurrent DM and CLD are also associated with worse clinical outcomes with respect to mortality, the occurrence of hepatic decompensation, and the development of hepatocellular carcinoma (HCC). Unfortunately, early diagnosis and optimal treatment of DM can be challenging, due to the lack of established clinical guidelines as well as the medical complexity of this patient population. We conducted an exploratory review of relevant literature to provide an up-to-date review for internists and hepatologists caring for this patient population. We reviewed the epidemiological and pathophysiological associations between DM and CLD, the impact of insulin resistance on the progression and manifestations of CLD, the pathogenesis of hepatogenic diabetes, as well as the practical challenges in diagnosis and monitoring of DM in this patient population. We also reviewed the latest clinical evidence on various pharmacological antihyperglycemic therapies with an emphasis on liver disease-related clinical outcomes. Finally, we proposed an algorithm for managing DM in patients with CLD and discussed the clinical and research questions that remain to be addressed.
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Affiliation(s)
- Waihong Chung
- Division of Gastroenterology, Department of Medicine, Rhode Island Hospital, Providence, RI 02905, United States.
| | - Kittichai Promrat
- Division of Gastroenterology and Hepatology, Providence VA Medical Center, Providence, RI 02908, United States
| | - Jack Wands
- Liver Research Center, The Warren Alpert Medical School of Brown University, Providence, RI 02903, United States
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28
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Shin H, Taghavifar S, Salehi S, Joyce P, Gholamrezanezhad A. Current comments on contrast media administration in patients with renal insufficiency. Clin Imaging 2020; 69:37-44. [PMID: 32652456 DOI: 10.1016/j.clinimag.2020.06.040] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 06/07/2020] [Accepted: 06/26/2020] [Indexed: 01/10/2023]
Abstract
Contrast media administration has been associated with complications such as nephropathy, cardiovascular morbidity, and neurovascular events, particularly in patients with renal insufficiency. This association has been questioned in recent studies. This review was performed to summarize the most current evidence on contrast induced nephropathy (CIN), contributing factors, and considerations in patients with renal insufficiency. The risk of CIN was over-estimated by the previous studies, due to a lack of control groups or presence of non-randomized control groups, which led to a selection bias. However, the thresholds associated with an increased risk of CIN are controversial and require risk-benefit analysis on an individual basis. Regarding the administration of contrast media (CM) in the emergency setting, the majority of studies suggested that CM exposure does not meaningfully increase the risk of acute kidney injury in critically ill patients (including trauma patients). Several strategies have been suggested to reduce the risk of CIN, including volume expansion to increase renal blood flow, sodium bicarbonate or N-acetylcysteine administration, and use of low-osmolal contrast media in end-stage renal disease.
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Affiliation(s)
- Heeseop Shin
- Department of Radiology, Keck School of Medicine, University of Southern California (USC), Los Angeles, CA, USA
| | | | - Sana Salehi
- Department of Radiology, Keck School of Medicine, University of Southern California (USC), Los Angeles, CA, USA.
| | - Peter Joyce
- Department of Radiology, Keck School of Medicine, University of Southern California (USC), Los Angeles, CA, USA
| | - Ali Gholamrezanezhad
- Department of Radiology, Keck School of Medicine, University of Southern California (USC), Los Angeles, CA, USA
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29
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Schädle P, Tschritter O, Kellerer M. Metformin Associated Lactic Acidosis in Clinical Practice - A Case Series. Exp Clin Endocrinol Diabetes 2020; 129:842-847. [PMID: 32403137 DOI: 10.1055/a-1149-9030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
AIMS The aim of this case report is to specify the frequency and mortality of Metformin-Associated Lactic Acidosis (MALA) in emergency medicine, as the diagnosis seems to occur more often than estimated. METHODS To identify the subjects, we developed screening criteria for MALA. We measured the serum metformin concentration to confirm the diagnosis in all patients fulfilling these criteria. Retrospectively the patients were grouped according to individual risk (according to a defined risk score) and the application of renal replacement therapy. RESULTS From 2013 until 2018 we were able to identify 11 MALA patients revealing a frequency of 1:4,000 emergency patients. Six patients survived and five died in the follow-up. All three patients in the high-risk group died although all of them received renal replacement therapy. In the low-risk group (three patients, one with renal replacement therapy), all patients survived, while in the intermediate-risk group (five patients, one with renal replacement therapy) three patients survived and two died. Additional severe comorbidities also contributed to mortality. CONCLUSIONS Every patient matching the screening criteria of acute renal failure, lactic acidosis and continued intake of metformin can be considered a potential MALA case. A risk score assessment which includes severe comorbidities may help to identify high-risk individuals and should be evaluated in larger studies.To prevent MALA, patients should be trained to immediately interrupt their own metformin use when showing signs of volume depletion. Physicians should be aware of the additional risk factors such as co-medication with diuretics, ACE (angiotensin converting enzyme) ACE inhibitors and NSAIDs (non steroidal anti inflammatory drugs).
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Affiliation(s)
- Philipp Schädle
- Centre of Internal Medicine I, Marienhospital Stuttgart, Vinzenz von Paul Kliniken, Stuttgart, Germany
| | - Otto Tschritter
- Centre of Internal Medicine I, Marienhospital Stuttgart, Vinzenz von Paul Kliniken, Stuttgart, Germany.,Emergency Department, Zollernalb Klinikum gGmbH, Balingen, Germany
| | - Monika Kellerer
- Centre of Internal Medicine I, Marienhospital Stuttgart, Vinzenz von Paul Kliniken, Stuttgart, Germany
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30
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Kwon S, Kim YC, Park JY, Lee J, An JN, Kim CT, Oh S, Park S, Kim DK, Oh YK, Kim YS, Lim CS, Lee JP. The Long-term Effects of Metformin on Patients With Type 2 Diabetic Kidney Disease. Diabetes Care 2020; 43:948-955. [PMID: 32132005 DOI: 10.2337/dc19-0936] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 02/09/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Metformin is the first pharmacological option for treating type 2 diabetes. However, the use of this drug is not recommended in individuals with impaired kidney function because of the perceived risk of lactic acidosis. We aimed to assess the efficacy and safety of metformin in patients with type 2 diabetic kidney disease (DKD). RESEARCH DESIGN AND METHODS We conducted a retrospective observational cohort study of 10,426 patients with type 2 DKD from two tertiary hospitals. The primary outcomes were all-cause mortality and end-stage renal disease (ESRD) progression. The secondary outcome was metformin-associated lactic acidosis. Taking into account the possibility that patients with less severe disease were prescribed metformin, propensity score matching (PSM) was conducted. RESULTS All-cause mortality and incident ESRD were lower in the metformin group according to the multivariate Cox analysis. Because the two groups had significantly different baseline characteristics, PSM was performed. After matching, metformin usage was still associated with lower all-cause mortality (adjusted hazard ratio [aHR] 0.65; 95% CI 0.57-0.73; P < 0.001) and ESRD progression (aHR 0.67; 95% CI 0.58-0.77; P < 0.001). Only one event of metformin-associated lactic acidosis was recorded. In both the original and PSM groups, metformin usage did not increase the risk of lactic acidosis events from all causes (aHR 0.92; 95% CI 0.668-1.276; P = 0.629). CONCLUSIONS In the present retrospective study, metformin usage in advanced chronic kidney disease (CKD) patients, especially those with CKD 3B, decreased the risk of all-cause mortality and incident ESRD. Additionally, metformin did not increase the risk of lactic acidosis. However, considering the remaining biases even after PSM, further randomized controlled trials are needed to change real-world practice.
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Affiliation(s)
- Soie Kwon
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Yong Chul Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Jae Yoon Park
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Korea
| | - Jeonghwan Lee
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Jung Nam An
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Gyeonggi-do, Korea
| | - Clara Tammy Kim
- Institute of Life and Death Studies, Hallym University, Chuncheon, Korea
| | - Sohee Oh
- Department of Biostatistics, Seoul Metropolitan Government, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Seokwoo Park
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Dong Ki Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Yun Kyu Oh
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Yon Su Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Chun Soo Lim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jung Pyo Lee
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea .,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
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31
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Hur KY, Kim MK, Ko SH, Han M, Lee DW, Kwon HS. Metformin treatment for patients with diabetes and chronic kidney disease: A Korean Diabetes Association and Korean Society of Nephrology consensus statement. Kidney Res Clin Pract 2020; 39:32-39. [PMID: 32138474 PMCID: PMC7105629 DOI: 10.23876/j.krcp.20.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 02/03/2020] [Accepted: 02/09/2020] [Indexed: 01/21/2023] Open
Abstract
The safety of metformin use for patients with type 2 diabetes mellitus (T2DM) and advanced kidney disease is controversial, and more recent guidelines have suggested that metformin be used cautiously in this group until more definitive evidence concerning its safety is available. The Korean Diabetes Association and the Korean Society of Nephrology have agreed on consensus statements concerning metformin use for patients with T2DM and renal dysfunction, particularly when these patients undergo imaging studies using iodinated contrast media (ICM). Metformin can be used safely when the estimated glomerular filtration rate (eGFR) is ≥ 45 mL/min/1.73 m2. If the eGFR is between 30 and 44 mL/min/1.73 m2, metformin treatment should not be started. If metformin is already in use, a daily dose of ≤ 1,000 mg is recommended. Metformin is contraindicated when the eGFR is < 30 mL/min/1.73 m2. Renal function should be evaluated prior to any ICM-related procedures. During procedures involving intravenous administration of ICM, metformin should be discontinued starting the day of the procedures and up to 48 hours post-procedures if the eGFR is < 60 mL/min/1.73 m2.
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Affiliation(s)
- Kyu Yeon Hur
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Mee Kyoung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Hyun Ko
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea
| | - Miyeun Han
- Division of Nephrology, Department of Internal Medicine, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Republic of Korea
| | - Dong Won Lee
- Division of Nephrology, Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Republic of Korea
| | - Hyuk-Sang Kwon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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32
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Hur KY, Kim MK, Ko SH, Han M, Lee DW, Kwon HS. Metformin Treatment for Patients with Diabetes and Chronic Kidney Disease: A Korean Diabetes Association and Korean Society of Nephrology Consensus Statement. Diabetes Metab J 2020; 44:3-10. [PMID: 32097995 PMCID: PMC7043977 DOI: 10.4093/dmj.2020.0004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 01/23/2020] [Indexed: 02/02/2023] Open
Abstract
The safety of metformin use for patients with type 2 diabetes mellitus (T2DM) and advanced kidney disease is controversial, and more recent guidelines have suggested that metformin be used cautiously in this group until more definitive evidence concerning its safety is available. The Korean Diabetes Association and the Korean Society of Nephrology have agreed on consensus statements concerning metformin use for patients with T2DM and renal dysfunction, particularly when these patients undergo imaging studies using iodinated contrast media (ICM). Metformin can be used safely when the estimated glomerular filtration rate (eGFR) is ≥45 mL/min/1.73 m². If the eGFR is between 30 and 44 mL/min/1.73 m², metformin treatment should not be started. If metformin is already in use, a daily dose of ≤1,000 mg is recommended. Metformin is contraindicated when the eGFR is <30 mL/min/1.73 m². Renal function should be evaluated prior to any ICM-related procedures. During procedures involving intravenous administration of ICM, metformin should be discontinued starting the day of the procedures and up to 48 hours post-procedures if the eGFR is <60 mL/min/1.73 m².
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Affiliation(s)
- Kyu Yeon Hur
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Mee Kyoung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Hyun Ko
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Miyeun Han
- Division of Nephrology, Department of Internal Medicine, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Dong Won Lee
- Division of Nephrology, Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Korea.
| | - Hyuk Sang Kwon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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33
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Akhter MS, Uppal P. Toxicity of Metformin and Hypoglycemic Therapies. Adv Chronic Kidney Dis 2020; 27:18-30. [PMID: 32146997 DOI: 10.1053/j.ackd.2019.08.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 08/01/2019] [Indexed: 12/15/2022]
Abstract
Metformin along with other antidiabetic medications provide benefit to patients in the treatment of type 2 diabetes mellitus, but caution is advised in certain scenarios to avoid toxicity in kidney disease. Renal dosing, monitoring of kidney function, and evaluating the risk of developing serious side effects are warranted with some agents. The available literature with regard to incidence of adverse events and toxicity of hypoglycemic therapies is reviewed.
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Gosmanova EO, Shahzad SR, Sumida K, Kovesdy CP, Gosmanov AR. Metformin is associated with increase in lactate level in elderly patients with type 2 diabetes and CKD stage 3: A case-control study. J Diabetes Complications 2020; 34:107474. [PMID: 31677983 DOI: 10.1016/j.jdiacomp.2019.107474] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 10/24/2019] [Accepted: 10/25/2019] [Indexed: 01/01/2023]
Abstract
The FDA has recently endorsed metformin use in patients with T2D and stage 3 CKD (CKD3). However, metformin safety in elderly individuals is unknown. The aim of this study was to identify frequency and risk factors of lactic acid (LA) elevation in ambulatory elderly male US veterans with stable diabetic CKD3 treated with metformin. We studied 92 patients with non-diabetic CKD3 (Group1), diabetic CKD3 not on metformin (Group2) and diabetic CKD3 on metformin (Group 3). Mean LA levels were similar at 1.3 ± 0.3 and 1.3 ± 0.4 mmol/L in Groups 1 and 2, respectively; while, LA was significantly higher in Group 3 (2.1 ± 1.0 mmol/L, P < .001). Only 1 patient in each Groups 1 (4%) and 2 (4%) had hyperlactatemia (LA > 2.0 mmol/L), as compared with 17 (42.5%) patients in Group 3 (P < .05). No differences in age, BMI, eGFR, metformin dosage, and HbA1c were seen in Group 3 patients with and without hyperlactatemia. In the multivariate logistic regression analyses, metformin use was the only factor significantly associated with hyperlactatemia (adjusted OR 25.48, P < .005). In conclusion, metformin therapy is associated with increased risk of hyperlactatemia in elderly men with diabetic CKD3.
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Affiliation(s)
- Elvira O Gosmanova
- Nephrology Section, Stratton VA Medical Center, Albany, NY, United States of America; Department of Medicine, Albany Medical College, Albany, NY, United States of America
| | - Sheikh R Shahzad
- Department of Medicine, Albany Medical College, Albany, NY, United States of America
| | - Keiichi Sumida
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States of America
| | - Csaba P Kovesdy
- Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States of America; Nephrology Section, Memphis VA Medical Center, Memphis, TN, United States of America
| | - Aidar R Gosmanov
- Endocrinology Section, Stratton VA Medical Center, Albany, NY, United States of America; Department of Medicine, Albany Medical College, Albany, NY, United States of America.
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35
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Molenaar RJ, van Hattum JW, Brummelhuis IS, Oddens JR, Savci-Heijink CD, Boevé ER, van der Meer SA, Witjes JF, Pollak MN, de Reijke TM, Wilmink JW. Study protocol of a phase II clinical trial of oral metformin for the intravesical treatment of non-muscle invasive bladder cancer. BMC Cancer 2019; 19:1133. [PMID: 31752752 PMCID: PMC6873510 DOI: 10.1186/s12885-019-6346-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 11/07/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Non-muscle-invasive bladder cancer (NMIBC) is the most common neoplasm of the urinary tract and requires life-long invasive surveillance to detect disease recurrence. Currently, there are no effective oral therapies that delay disease recurrence or progression. We recently demonstrated that in mice, metformin accumulates unchanged in the urine. Urothelial cells are exposed to metformin concentrations ~ 240-fold higher than in serum. This was effective in the treatment of mouse bladder cancer models. METHODS We describe the protocol of a multi-centre, open-label, phase II clinical trial of metformin in up to 49 evaluable patients with intermediate-risk NMIBC with the aim to determine the overall response to administration of oral metformin for 3 months on a marker tumour deliberately left following transurethral resection of multiple, papillary NMIBC tumours. All patients will receive metformin orally at doses up to 3000 mg per day. Metformin treatment will start within 2 weeks following transurethral resection of all tumours except one marker lesion. After 3 months of metformin treatment, the effect of metformin on the marker lesion is evaluated by cystoscopy and biopsy under anaesthesia. Residual tumour, if present at this evaluation, will be resected. In case of complete disappearance of the marker lesion, the former tumour area will be biopsied. The primary outcome is the complete response rate of the marker lesion, as determined by decentralised scoring of pre- and post-treatment cystoscopy images by expert independent urologists. Secondary outcomes are the partial response rate, overall safety of metformin and the duration of the time to recurrence. DISCUSSION Preclinical studies show the potential role of oral metformin treatment in the management of NMIBC. It could offer an alternative to current adjuvant intravesical treatment. If positive, the reported results of this study could warrant further phase III trials to compare the efficacy of metformin against current treatments of intravesical installations with chemotherapy or Bacillus Calmette-Guérin (BCG). TRIAL REGISTRATION This trial is registered in ClinicalTrials.gov under NCT03379909.
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Affiliation(s)
- Remco J Molenaar
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Jons W van Hattum
- Department of Urology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, 1105, AZ, Amsterdam, The Netherlands.
| | - Iris S Brummelhuis
- Department of Urology, Jeroen Bosch Ziekenhuis, Henri Dunantstraat 1, 5223 GZ, 's-Hertogenbosch, The Netherlands
| | - Jorg R Oddens
- Department of Urology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, 1105, AZ, Amsterdam, The Netherlands
| | - C Dilara Savci-Heijink
- Department of Medical Pathology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Egbert R Boevé
- Department of Urology, Sint Franciscus Hospital, Kleiweg 500, 3045, PM, Rotterdam, The Netherlands
| | - Saskia A van der Meer
- Department of Urology, Jeroen Bosch Ziekenhuis, Henri Dunantstraat 1, 5223 GZ, 's-Hertogenbosch, The Netherlands
| | - J Fred Witjes
- Department of Urology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525, GA, Nijmegen, The Netherlands
| | - Michael N Pollak
- Departments of Oncology and Medicine, McGill University, McIntyre Medical Building, 3655 Sir William Osler, Montreal, Quebec, H3G 1Y6, Canada.,Segal Cancer Centre, Jewish General Hospital, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec, H3T 1E2, Canada
| | - Theo M de Reijke
- Department of Urology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, 1105, AZ, Amsterdam, The Netherlands
| | - Johanna W Wilmink
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
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36
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Salvatore T, Pafundi PC, Marfella R, Sardu C, Rinaldi L, Monaco L, Ricozzi C, Imbriani S, Nevola R, Adinolfi LE, Sasso FC. Metformin lactic acidosis: Should we still be afraid? Diabetes Res Clin Pract 2019; 157:107879. [PMID: 31618624 DOI: 10.1016/j.diabres.2019.107879] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 09/27/2019] [Accepted: 10/11/2019] [Indexed: 12/11/2022]
Abstract
Metformin, the first choice drug for type 2 diabetes treatment in all stages of therapy, and one of the most widely prescribed anti-hyperglycemic agents worldwide, represents a rare example of an old drug which continues to display new beneficial effects in various fields. However, lactic acidosis (LA) persists as a serious adverse effect. LA incidence is low and is not necessarily determined by the administration of metformin. Unfortunately, the concern for this complication has negatively affected the drug use, particularly in chronic kidney disease, which may impair drug excretion, and in congestive heart failure and chronic liver disease, which may promote lactate accumulation. This review describes how not only these historical contraindications have been considerably scaled back, though rather a recent large body of evidence supports a protective effect of biguanide on kidney, heart and liver and, maybe, against lactic acidosis itself. It is worthy to slow down both contraindications and precautions to metformin use, not to deprive a significant number of diabetic patients, as those with kidney, heart and liver comorbidities, from its potential benefits, and not to hamper in the near future the putative advantages in a wide spectrum of conditions outside of diabetes.
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Affiliation(s)
- Teresa Salvatore
- Unit of Internal Medicine, Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138 Naples, Italy.
| | - Pia Clara Pafundi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138 Naples, Italy.
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138 Naples, Italy.
| | - Celestino Sardu
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138 Naples, Italy.
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138 Naples, Italy.
| | - Lucio Monaco
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138 Naples, Italy.
| | - Carmen Ricozzi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138 Naples, Italy.
| | - Simona Imbriani
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138 Naples, Italy.
| | - Riccardo Nevola
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138 Naples, Italy.
| | - Luigi Elio Adinolfi
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138 Naples, Italy.
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138 Naples, Italy.
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Jung J, Cho YY, Jung JH, Kim KY, Kim HS, Baek JH, Hahm JR, Cho HS, Kim SK. Are patients with mild to moderate renal impairment on metformin or other oral anti-hyperglycaemic agents at increased risk of contrast-induced nephropathy and metabolic acidosis after radiocontrast exposure? Clin Radiol 2019; 74:651.e1-651.e6. [PMID: 31202566 DOI: 10.1016/j.crad.2019.05.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 05/16/2019] [Indexed: 10/26/2022]
Abstract
AIM To investigate whether the use of metformin during computed tomography (CT) with radiocontrast agents increases the risk of contrast-induced nephropathy (CIN) and metabolic acidosis after CT in type 2 diabetes patients with mild to moderate renal failure. MATERIALS AND METHODS Patient records from January 2015 to December 2017 were reviewed retrospectively. A total of 374 patients were included in the final analysis. Of them, 157 patients received metformin, and 217 patients were taking other oral hypoglycaemic agents (OHAs) during radiocontrast administration. RESULTS No significant difference in CIN incidence was observed between the metformin use group and the other OHAs group (p=0.085). Metabolic acidosis after CT was seen in 91 (58%) patients who used metformin and 141 (65%) patients who were taking other OHAs. There was no relationship between metabolic acidosis after CT and the use of metformin (p=0.195). Metabolic acidosis after radiocontrast agent exposure was associated with malignant disease, low serum albumin level, and low serum total CO2 level at baseline. CONCLUSION These data show that other factors, but not metformin use, are associated with metabolic acidosis after radiocontrast agent exposure in patients with reduced renal function. These data support current recommendations that there is no need to discontinue metformin before CT using radiocontrast agents in patients with mild to moderate renal failure.
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Affiliation(s)
- J Jung
- Gyeongsang National University School of Medicine Jinju, Republic of Korea; Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea; Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - Y Y Cho
- Gyeongsang National University School of Medicine Jinju, Republic of Korea; Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea; Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
| | - J H Jung
- Gyeongsang National University School of Medicine Jinju, Republic of Korea; Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea; Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
| | - K Y Kim
- Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
| | - H S Kim
- Gyeongsang National University School of Medicine Jinju, Republic of Korea; Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea; Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - J-H Baek
- Gyeongsang National University School of Medicine Jinju, Republic of Korea; Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea; Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - J R Hahm
- Gyeongsang National University School of Medicine Jinju, Republic of Korea; Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea; Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
| | - H S Cho
- Gyeongsang National University School of Medicine Jinju, Republic of Korea; Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea; Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
| | - S K Kim
- Gyeongsang National University School of Medicine Jinju, Republic of Korea; Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea; Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea.
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Tanner C, Wang G, Liu N, Andrikopoulos S, Zajac JD, Ekinci EI. Metformin: time to review its role and safety in chronic kidney disease. Med J Aust 2019; 211:37-42. [PMID: 31187887 DOI: 10.5694/mja2.50239] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
■Metformin is recommended as first-line therapy for type 2 diabetes because of its safety, low cost and potential cardiovascular benefits. ■The use of metformin was previously restricted in people with chronic kidney disease (CKD) - a condition that commonly coexists with diabetes - due to concerns over drug accumulation and metformin-associated lactic acidosis. ■There are limited data from observational studies and small randomised controlled trials to suggest that metformin, independent of its antihyperglycaemic effects, may be associated with lower risk of myocardial infarction, stroke and all-cause mortality in people with type 2 diabetes and CKD. ■Research into the risk of metformin-associated lactic acidosis in CKD has previously been limited and conflicting, resulting in significant variation across international guidelines on the safe prescribing and dosing of metformin at different stages of renal impairment. ■Present-day large scale cohort studies now provide supporting evidence for the safe use of metformin in mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-60 mL/min/1.73m2 ). However, prescribing metformin in people with severe renal impairment (eGFR < 30 mL/min/1.73m2 ) remains a controversial issue. Due to observed increased risk of lactic acidosis and all-cause mortality in people with type 2 diabetes and severe renal impairment, it is generally recommended that metformin is discontinued if renal function falls below this level or during acute renal deterioration.
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Affiliation(s)
| | | | | | | | - Jeffrey D Zajac
- Austin Health, Melbourne, VIC.,University of Melbourne, Melbourne, VIC
| | - Elif I Ekinci
- Austin Health, Melbourne, VIC.,University of Melbourne, Melbourne, VIC
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39
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Adibkia K, Ghajar S, Osouli-Bostanabad K, Balaei N, Emami S, Barzegar-Jalali M. Novel Gliclazide Electrosprayed Nano-Solid Dispersions: Physicochemical Characterization and Dissolution Evaluation. Adv Pharm Bull 2019; 9:231-240. [PMID: 31380248 PMCID: PMC6664122 DOI: 10.15171/apb.2019.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Revised: 01/11/2019] [Accepted: 04/14/2019] [Indexed: 11/18/2022] Open
Abstract
Purpose: In the current study, electrospraying was directed as a novel alternative approach to improve the physicochemical attributes of gliclazide (GLC), as a poorly water-soluble drug, by creating nanocrystalline/amorphous solid dispersions (ESSs). Methods: ESSs were formulated using Eudragit® RS100 and polyethylene glycol (PEG) 6000 as polymeric carriers at various drug: polymer ratios (i.e. 1:5 and 1:10) with different total solution concentrations of 10, 15, and 20% w/v. Morphological, physicochemical, and in-vitro release characteristics of the developed formulations were assessed. Furthermore, GLC dissolution behaviors from ESSs were fitted to various models in order to realize the drug release mechanism. Results: Field emission scanning electron microscopy analyses revealed that the size and morphology of the ESSs were affected by the drug: polymer ratios and solution concentrations. The polymer ratio augmentation led to increase in the particle size while the solution concentration enhancement yielded in a fiber establishment. Differential scanning calorimetry and powder X-ray diffraction investigations demonstrated that the ESSs were present in an amorphous state. Furthermore, the in vitro drug release studies depicted that the samples prepared employing PEG 6000 as carrier enhanced the dissolution rate and the model that appropriately fitted the release behavior of ESSs was Weibull model, where demonstrating a Fickian diffusion as the leading release mechanism. Fourier-transform infrared spectroscopy results showed a probability of complexation or hydrogen bonding, development between GLC and the polymers in the solid state. Conclusion: Hence the electrospraying system avails the both nanosizing and amorphization advantages, therefore, it can be efficiently applied to formulating of ESSs of BCS Class II drugs.
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Affiliation(s)
- Khosro Adibkia
- Research Center for Pharmaceutical Nanotechnology and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Solmaz Ghajar
- Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
- Students Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Karim Osouli-Bostanabad
- Students Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Balaei
- Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
- Students Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahram Emami
- Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
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40
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Boada Fernández del Campo C, Rodríguez Jimenez C, García Saiz M, Aldea Perona A, Sanz Álvarez E, Fernández Quintana E, García Sanchez-Colomer M, Huidobro Amaro S, Arbesú Cruz A, Jimenez Sosa A. Metformin-associated hyperlactacidaemia acidosis: Diagnosis rate in standard clinical practice and its relationship with renal failure. Rev Clin Esp 2019. [DOI: 10.1016/j.rceng.2019.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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41
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Gómez-Peralta F, Abreu C. Metformin-associated lactic acidosis, a ghost or a murderer? Rev Clin Esp 2019. [DOI: 10.1016/j.rceng.2019.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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42
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Acidosis láctica asociada a metformina, ¿un fantasma o un asesino? Rev Clin Esp 2019; 219:256-257. [DOI: 10.1016/j.rce.2019.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 01/02/2019] [Indexed: 11/24/2022]
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Boada Fernández del Campo C, Rodríguez Jimenez C, García Saiz M, Aldea Perona A, Sanz Álvarez E, Fernández Quintana E, García Sanchez-Colomer M, Huidobro Amaro S, Arbesú Cruz A, Jimenez Sosa A. Acidosis con hiperlactacidemia por metformina: frecuencia de su diagnóstico en la práctica clínica habitual y relación con la insuficiencia renal. Rev Clin Esp 2019; 219:236-242. [DOI: 10.1016/j.rce.2018.11.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 11/09/2018] [Accepted: 11/12/2018] [Indexed: 11/26/2022]
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Pedrós C, Ávila M, Gómez-Lumbreras A, Manríquez M, Morros R. Lactic acidosis associated with metformin in patients with moderate to severe chronic kidney disease: study protocol for a multicenter population-based case-control study using health databases. BMC Nephrol 2019; 20:193. [PMID: 31146690 PMCID: PMC6543584 DOI: 10.1186/s12882-019-1389-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 05/16/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The use of metformin in patients with type 2 diabetes mellitus has been associated with lactic acidosis. However, the information available in patients with moderate-severe chronic kidney disease is scarce. METHODS The ALIMAR-C2 study is a case-control study to assess the association between metformin and lactic acidosis in patients with type 2 diabetes mellitus and moderate-severe chronic kidney disease. The study will be performed with computerized registered electronic health records from eight Spanish hospitals linked to their corresponding primary care health areas from 2010 to 2016, comprising approximately 22.1 million person-years of follow-up. Logistic regression will be used to assess the crude and adjusted risk of lactic acidosis associated with metformin use overall and stratifying by use and dose categories, and chronic kidney disease stage. The overall case fatality rate of lactic acidosis, as well as the case fatality rate stratified by chronic kidney disease stage, will be calculated. DISCUSSION The ALIMAR-C2 study will provide useful information about the risk of lactic acidosis in type 2 diabetes mellitus patients with renal impairment using metformin.
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Affiliation(s)
- Consuelo Pedrós
- Clinical Pharmacology Department, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Mónica Ávila
- Clinical Research and Clinical Trials Unit, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
| | - Ainhoa Gómez-Lumbreras
- Medicines Research Unit, Foundation University Institute for Primary Health Care Research Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain.,Department of Medical Sciences, Girona University, Girona, Spain
| | - Marcela Manríquez
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Rosa Morros
- Medicines Research Unit, Foundation University Institute for Primary Health Care Research Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain.,Departament de Farmacologia, Terapèutica i Toxicologia, Universitat Autònoma de Barcelona, Barcelona, Spain.,Catalan Health Institute, Barcelona, Spain
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Pipeleers L, Wissing KM, Hilbrands R. Acid-base and electrolyte disturbances in patients with diabetes mellitus. Acta Clin Belg 2019; 74:28-33. [PMID: 30470164 DOI: 10.1080/17843286.2018.1546983] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Lissa Pipeleers
- Departments of Nephrology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Karl Martin Wissing
- Departments of Nephrology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Robert Hilbrands
- Departments of Nephrology, Universitair Ziekenhuis Brussel, Brussels, Belgium
- Departments of Diabetology, Universitair Ziekenhuis Brussel, Brussels, Belgium
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Incidencia, factores relacionados con la presentación, evolución y mortalidad de la acidosis láctica asociada a metformina en el área sanitaria de un hospital de tercer nivel. Nefrologia 2019; 39:35-43. [DOI: 10.1016/j.nefro.2018.04.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 02/13/2018] [Accepted: 04/04/2018] [Indexed: 11/22/2022] Open
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Corremans R, Vervaet BA, D'Haese PC, Neven E, Verhulst A. Metformin: A Candidate Drug for Renal Diseases. Int J Mol Sci 2018; 20:E42. [PMID: 30583483 PMCID: PMC6337137 DOI: 10.3390/ijms20010042] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 12/12/2018] [Accepted: 12/20/2018] [Indexed: 12/11/2022] Open
Abstract
Over the past decades metformin has been the optimal first-line treatment for type 2 diabetes mellitus (T2DM). Only in the last few years, it has become increasingly clear that metformin exerts benign pleiotropic actions beyond its prescribed use and ongoing investigations focus on a putative beneficial impact of metformin on the kidney. Both acute kidney injury (AKI) and chronic kidney disease (CKD), two major renal health issues, often result in the need for renal replacement therapy (dialysis or transplantation) with a high socio-economic impact for the patients. Unfortunately, to date, effective treatment directly targeting the kidney is lacking. Metformin has been shown to exert beneficial effects on the kidney in various clinical trials and experimental studies performed in divergent rodent models representing different types of renal diseases going from AKI to CKD. Despite growing evidence on metformin as a candidate drug for renal diseases, in-depth research is imperative to unravel the molecular signaling pathways responsible for metformin's renoprotective actions. This review will discuss the current state-of-the-art literature on clinical and preclinical data, and put forward potential cellular mechanisms and molecular pathways by which metformin ameliorates AKI/CKD.
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Affiliation(s)
- Raphaëlle Corremans
- Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2000 Antwerp, Belgium.
| | - Benjamin A Vervaet
- Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2000 Antwerp, Belgium.
| | - Patrick C D'Haese
- Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2000 Antwerp, Belgium.
| | - Ellen Neven
- Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2000 Antwerp, Belgium.
| | - Anja Verhulst
- Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, 2000 Antwerp, Belgium.
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Deden LN, Aarts EO, Aelfers SCW, van Borren MMGJ, Janssen IMC, Berends FJ, de Boer H. Risk of Metformin-Associated Lactic Acidosis (MALA) in Patients After Gastric Bypass Surgery. Obes Surg 2018; 28:1080-1085. [PMID: 29058235 DOI: 10.1007/s11695-017-2974-1] [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] [Indexed: 12/20/2022]
Abstract
BACKGROUND Pharmacokinetic data suggest that the risk of metformin-associated lactic acidosis (MALA) may be increased after Roux-en-Y gastric bypass (RYGB) surgery. The aim of this study was to examine the impact of metformin on plasma lactate levels before and after RYGB surgery. METHODS Retrospective study of plasma lactate levels before and 3 months after RYGB surgery in patients with type 2 diabetes mellitus (T2DM) not using metformin (MET-0, N = 58), on a stable dose (MET-S, N = 138), or on a decreasing dose (MET-D, N = 85) of metformin. RESULTS Preoperatively, lactate levels were similar in patients on metformin (1.8 ± 0.05 mmol/L) and those not on metformin (1.7 ± 0.08 mmol/L), P = 0.21. Three months postoperatively, lactate levels had decreased in all groups (P < 0.001) to 1.3 ± 0.07 (SE), 1.4 ± 0.05, and 1.2 ± 0.05 mmol/l in MET-0, MET-S, and MET-D, respectively. Lactate levels differed between the groups (P = 0.03), with the lowest level in MET-D. The number of patients with hyperlactatemia (lactate > 2 mmol/l) decreased from 31 to 14%, from 22 to 8.6%, and from 26 to 4.7% in MET-S, MET-0, and MET-D, respectively. CONCLUSION Mild hyperlactatemia (lactate > 2 mmol/l) is common in morbidly obese patients with T2DM. It is probably related to increase lactate production by adipocytes. Lactate levels decreased after RYGB-induced weight loss, irrespective of the use of metformin. We therefore conclude that there is no need for routinely lowering of the metformin dose after uncomplicated RYGB surgery, as long as normal renal function is preserved.
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Affiliation(s)
- Laura N Deden
- Department of Surgery, Rijnstate Hospital, Wagnerlaan 55, 6800 TA, Arnhem, The Netherlands. .,Vitalys Clinic, Velp, The Netherlands.
| | - Edo O Aarts
- Department of Surgery, Rijnstate Hospital, Wagnerlaan 55, 6800 TA, Arnhem, The Netherlands.,Vitalys Clinic, Velp, The Netherlands
| | - Stephanie C W Aelfers
- Department of Surgery, Rijnstate Hospital, Wagnerlaan 55, 6800 TA, Arnhem, The Netherlands.,Vitalys Clinic, Velp, The Netherlands
| | | | - Ignace M C Janssen
- Department of Surgery, Rijnstate Hospital, Wagnerlaan 55, 6800 TA, Arnhem, The Netherlands.,Vitalys Clinic, Velp, The Netherlands
| | - Frits J Berends
- Department of Surgery, Rijnstate Hospital, Wagnerlaan 55, 6800 TA, Arnhem, The Netherlands.,Vitalys Clinic, Velp, The Netherlands
| | - Hans de Boer
- Departments of Internal Medicine, Rijnstate Hospital, Arnhem, The Netherlands
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Metformin prevents the development of severe chronic kidney disease and its associated mineral and bone disorder. Kidney Int 2018; 94:102-113. [DOI: 10.1016/j.kint.2018.01.027] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 01/17/2018] [Accepted: 01/25/2018] [Indexed: 12/15/2022]
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50
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Lazarus B, Wu A, Shin JI, Sang Y, Alexander GC, Secora A, Inker LA, Coresh J, Chang AR, Grams ME. Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function: A Community-Based Cohort Study. JAMA Intern Med 2018; 178:903-910. [PMID: 29868840 PMCID: PMC6145716 DOI: 10.1001/jamainternmed.2018.0292] [Citation(s) in RCA: 120] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/06/2018] [Indexed: 01/07/2023]
Abstract
Importance Approximately 1 million patients in the United States with type 2 diabetes mellitus and mild-to-moderate kidney disease do not receive guideline-directed therapy with metformin. This may reflect uncertainty regarding the risk of acidosis in patients with chronic kidney disease. Objective To quantify the association between metformin use and hospitalization with acidosis across the range of estimated glomerular filtration rate (eGFR), accounting for change in eGFR stage over time. Design, Setting, and Participants Community-based cohort of 75 413 patients with diabetes in Geisinger Health System, with time-dependent assessment of eGFR stage from January 2004 until January 2017. Results were replicated in 67 578 new metformin users and 14 439 new sulfonylurea users from 2010 to 2015, sourced from 350 private US health systems. Exposures Metformin use. Main Outcomes and Measures Hospitalization with acidosis (International Classification of Diseases, Ninth Revision, Clinical Modification code of 276.2). Results In the primary cohort (n = 75 413), mean (SD) patient age was 60.4 (15.5) years, and 51% (n = 38 480) of the participants were female. There were 2335 hospitalizations with acidosis over a median follow-up of 5.7 years (interquartile range, 2.5-9.9 years). Compared with alternative diabetes management, time-dependent metformin use was not associated with incident acidosis overall (adjusted hazard ratio [HR], 0.98; 95% CI, 0.89-1.08) or in patients with eGFR 45 to 59 mL/min/1.73 m2 (adjusted HR, 1.16; 95% CI, 0.95-1.41) and eGFR 30 to 44 mL/min/1.73 m2 (adjusted HR, 1.09; 95% CI, 0.83-1.44). On the other hand, metformin use was associated with an increased risk of acidosis at eGFR less than 30 mL/min/1.73 m2 (adjusted HR, 2.07; 95% CI, 1.33-3.22). Results were consistent when new metformin users were compared with new sulfonylurea users (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 0.77; 95% CI, 0.29-2.05), in a propensity-matched cohort (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 0.71; 95% CI, 0.45-1.12), when baseline insulin users were excluded (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 1.16; 95% CI, 0.87-1.57), and in the replication cohort (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 0.86; 95% CI, 0.37-2.01). Conclusions and Relevance In 2 real-world clinical settings, metformin use was associated with acidosis only at eGFR less than 30 mL/min/1.73 m2. Our results support cautious use of metformin in patients with type 2 diabetes and eGFR of at least 30 mL/min/1.73 m2.
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Affiliation(s)
- Benjamin Lazarus
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Division of Nephrology, Monash Medical Centre, Clayton, Australia
| | - Aozhou Wu
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Jung-Im Shin
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Yingying Sang
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - G. Caleb Alexander
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Alex Secora
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Lesley A. Inker
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Alex R. Chang
- Kidney Health Research Institute, Geisinger Health System, Danville, Pennsylvania
| | - Morgan E. Grams
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland
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