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Liu X, Li X, An P, Gao Q, Zhao Y, Shi X, Wu X. Metformin and risk factors for chronic kidney disease in a European population based on Mendelian randomization. Ren Fail 2025; 47:2486551. [PMID: 40289841 PMCID: PMC12039405 DOI: 10.1080/0886022x.2025.2486551] [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: 09/04/2024] [Revised: 01/30/2025] [Accepted: 03/11/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND Metformin, widely used for type 2 diabetes, raises concerns about its use in chronic kidney disease (CKD) due to risks like lactic acidosis and renal function impact. This study uses Mendelian randomization (MR) and summary data-based MR (SMR) to explore metformin's potential causal relationship with CKD and associated genes. METHODS We employed MR methods (MR-Egger, weighted median, IVW) and sensitivity analyses to explore the causal relationship between metformin and CKD. SMR was used to analyze eQTL and CKD data from the UK Biobank and FinnGen, intersecting these with metformin drug targets to identify genes associated with CKD. RESULTS MR analysis indicated that metformin may increase CKD risk (IVW model: OR = 144.67, p < 0.01). However, given the high OR value, additional studies are warranted to validate this finding. SMR identified genes ANPEP, STK11, ACACB, and RPS6KB as significantly associated with CKD risk. CONCLUSION The study suggests metformin could elevate CKD risk and identifies relevant genes. Clinicians should exercise caution when prescribing metformin, particularly for patients with renal issues. Further research is needed to confirm these findings and guide clinical practices.
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Affiliation(s)
- Xiaopei Liu
- Department of Traditional Chinese Medicine, Huangling Hospital of Traditional Chinese Medicine, Yan’an, Shaanxi, China
| | - Xingyao Li
- Department of Traditional Chinese Medicine, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Peng An
- Department of Traditional Chinese Medicine, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Qi Gao
- Department of Traditional Chinese Medicine, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Yanhong Zhao
- Department of Traditional Chinese Medicine, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Xingmin Shi
- Key Laboratory for Disease Prevention and Control and Health Promotion of Shaanxi Province, School of Public Health, Medical Science Center, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Xili Wu
- Department of Traditional Chinese Medicine, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
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Abbasi AB, Posselt A, Orandi BJ, Odorico JS, Stock PG. Obesity management before and after pancreas transplantation. Curr Opin Organ Transplant 2025:00075200-990000000-00180. [PMID: 40314343 DOI: 10.1097/mot.0000000000001226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
PURPOSE OF REVIEW We provide a review on the incidence, consequences, and management of obesity in patients before and after pancreas transplant. RECENT FINDINGS Obesity is common in patients with both type 1 and type 2 diabetes. Obesity at the time of pancreas transplant is associated with worse graft and patient survival, while weight gain after transplant is associated with insulin resistance and posttransplant diabetes. Currently, lifestyle interventions are the backbone of obesity management and can improve insulin sensitivity, but result in only modest weight loss. Metabolic and bariatric surgery (MBS) offers the potential for substantial and durable weight loss. Laparoscopic sleeve gastrectomy is the procedure of choice and can be performed safely both before and after pancreas transplant. Antiobesity medications (AOMs) may also be effective, but concerns remain regarding determine the safety and efficacy when used in pancreas transplant recipients. More evidence is needed to guide the use of AOMs and MBS in pancreas transplant recipients. SUMMARY Lifestyle interventions, MBS, and AOMs each have a role in managing obesity after pancreas transplantation. In light of limited evidence and unique challenges in pancreas transplant patients, obesity management in pancreas transplant patients requires an individualized approach that leverages multidisciplinary expertise.
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Affiliation(s)
- Ali B Abbasi
- Division of Transplantation, Department of Surgery, University of California San Francisco, San Francisco, California
| | - Andrew Posselt
- Division of Transplantation, Department of Surgery, University of California San Francisco, San Francisco, California
| | - Babak J Orandi
- Department of Surgery
- Departments of Medicine, NYU Grossman School of Medicine, New York, New York
| | - Jon S Odorico
- University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Peter G Stock
- Division of Transplantation, Department of Surgery, University of California San Francisco, San Francisco, California
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Ma Y, Zhao Y, Wei R, Qiao J, Luo J, Zhang L, Zhang J, Deng M, Yu Y, Wang W, Pan Q, Guo L. Economic costs and medications for diabetes in older patients in Beijing, China: electronic insurance data analysis. Front Pharmacol 2025; 16:1549244. [PMID: 40260392 PMCID: PMC12009719 DOI: 10.3389/fphar.2025.1549244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 03/19/2025] [Indexed: 04/23/2025] Open
Abstract
Background With the aging of population, the proportion of elderly patients with diabetes is gradually increasing, which poses challenges in the management and treatment of diabetes in this population. Methods The aim of the study was to investigate the temporal changes in the treatment regimens and medical expenditures in older patients with diabetes in Beijing, China. Data of patients with diabetes from the Beijing Medical Insurance Database with medical records from 2016 to 2018 were retrospectively analyzed. Primary and secondary outcomes included the number of medications, comorbidities, diabetes-related complications, the estimated annual drug cost, the treatment strategies for elderly diabetic patients, and the classes of drugs prescribed. Results Data of 598,440 patients with diabetes in 2018 revealed that 49.8% of the recruited patients were female among elderly patients (>65 years old). The most common comorbidity was hypertension (87.6%). Over the 3 years, about 4.51 medications, including 1.88 antiglycemic drugs and 2.63 non-antiglycemic drugs were prescribed in elderly patients. The mean total annual medication cost was ¥12,186 ($1,676), including ¥6,116 ($841) for antiglycemic drugs and ¥6,070 ($835) for non-antiglycemic drugs. Hypertension (cost ¥4,658, $640, mean medications 2.12 for elderly patients), dyslipidemia (¥5,044, $693, 1.70), and coronary heart disease (¥4,004, $550, 1.40) were the top three diseases that caused the increase in the cost and medications. Over the 3 years, more than 94% of elderly diabetic patients received at least one type of antiglycemic drugs, and the α-glucosidase inhibitors and premixed insulin are the most commonly prescribed hypoglycemic drugs and insulin, respectively. Conclusion Diabetes management in older patients faces challenges due to extensive variability. Medication analysis in this study found that the current situation of comprehensive control of diabetes in elderly patients is worrying, and the complexity of their medication is still on the increasing trend. It is important to select more appropriate antiglycemic drugs to economically benefit the patients and to control the progression of complications.
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Affiliation(s)
- Yanhua Ma
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yan Zhao
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Ran Wei
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Jingtao Qiao
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Jingyi Luo
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Lina Zhang
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Jie Zhang
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Mingqun Deng
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Yang Yu
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Weihao Wang
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Qi Pan
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Lixin Guo
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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ElSayed NA, McCoy RG, Aleppo G, Bajaj M, Balapattabi K, Beverly EA, Briggs Early K, Bruemmer D, Echouffo-Tcheugui JB, Ekhlaspour L, Gaglia JL, Garg R, Girotra M, Khunti K, Lal R, Lingvay I, Matfin G, Neumiller JJ, Pandya N, Pekas EJ, Pilla SJ, Polsky S, Segal AR, Seley JJ, Stanton RC, Bannuru RR. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2025. Diabetes Care 2025; 48:S181-S206. [PMID: 39651989 PMCID: PMC11635045 DOI: 10.2337/dc25-s009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2024]
Abstract
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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Zhao T, Yang Q, Feuerbacher JF, Yu B, Brinkmann C, Cheng S, Bloch W, Schumann M. Effects of exercise, metformin and their combination on glucose metabolism in individuals with abnormal glycaemic control: a systematic review and network meta-analysis. Br J Sports Med 2024; 58:1452-1460. [PMID: 39242178 DOI: 10.1136/bjsports-2024-108127] [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] [Accepted: 08/23/2024] [Indexed: 09/09/2024]
Abstract
OBJECTIVE To compare the efficacy of exercise, metformin and their combination on glucose metabolism in individuals with abnormal glycaemic control. DESIGN Systematic review and network meta-analysis. DATA SOURCES Embase, Web of Science, PubMed/MEDLINE and SPORTDiscus. ELIGIBILITY CRITERIA Randomised controlled trials involving exercise, metformin or their combined treatments in individuals with prediabetes or type 2 diabetes mellitus (T2DM) were included. Outcomes included haemoglobin A1c (HbA1c), 2-hour glucose during oral glucose tolerance test, fasting glucose, fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS 407 articles with 410 randomised controlled trials (n=33 802) were included. In prediabetes, the exercise showed greater efficacy than metformin on HbA1c levels (mean difference -0.16%, 95% CI (-0.23 to -0.09) vs -0.10%, 95% CI (-0.21 to 0.02)), 2-hour glucose (-0.68 mmol/L, 95% CI (-0.97 to -0.39) vs 0.01 mmol/L, 95% CI (-0.38 to 0.41)) and HOMA-IR (-0.54, 95% CI (-0.71 to -0.36) vs -0.23, 95% CI (-0.55 to 0.10)), while the efficacy on fasting glucose was comparable (-0.26 mmol/L, 95% CI (-0.32 to -0.19) vs -0.33 mmol/L, 95% CI (-0.45 to -0.21)). In T2DM, metformin was more efficacious than exercise on HbA1c (-0.88%, 95% CI (-1.07 to -0.69) vs -0.48%, 95% CI (-0.58 to -0.38)), 2-hour glucose (-2.55 mmol/L, 95% CI (-3.24 to -1.86) vs -0.97 mmol/L, 95% CI (-1.52 to -0.42)) and fasting glucose (-1.52 mmol/L, 95% CI (-1.73 to -1.31) vs -0.85 mmol/L, 95% CI (-0.96 to -0.74)); exercise+metformin also showed greater efficacy in improving HbA1c (-1.23%, 95% CI (-2.41 to -0.05)) and fasting glucose (-2.02 mmol/L, 95% CI (-3.31 to -0.74)) than each treatment alone. However, the efficacies were modified by exercise modality and metformin dosage. CONCLUSION Exercise, metformin and their combination are efficacious in improving glucose metabolism in both prediabetes and T2DM. The efficacy of exercise appears to be superior to metformin in prediabetes, but metformin appears to be superior to exercise in patients with T2DM. PROSPERO REGISTRATION NUMBER CRD42023400622.
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Affiliation(s)
- Tong Zhao
- Department of Molecular and Cellular Sports Medicine, German Sport University Cologne, Cologne, Germany
- Exercise Translational Medicine Centre, Shanghai Centre for Systems Biomedicine Shanghai, Shanghai Jiao Tong University, Shanghai, Shanghai, China
- Department of Physical Education, Shanghai Jiao Tong University, Shanghai, Shanghai, China
| | - Qize Yang
- Exercise Translational Medicine Centre, Shanghai Centre for Systems Biomedicine Shanghai, Shanghai Jiao Tong University, Shanghai, Shanghai, China
- Department of Physical Education, Shanghai Jiao Tong University, Shanghai, Shanghai, China
| | - Joshua F Feuerbacher
- Department of Molecular and Cellular Sports Medicine, German Sport University Cologne, Cologne, Germany
- Department of Sports Medicine and Exercise Therapy, Institute of Human Movement Science and Health, Chemnitz University of Technology, Chemnitz, Germany
| | - Bizhu Yu
- Department of Molecular and Cellular Sports Medicine, German Sport University Cologne, Cologne, Germany
| | - Christian Brinkmann
- Department of Preventive and Rehabilitative Sport Medicine, German Sport University Cologne, Cologne, Germany
| | - Sulin Cheng
- Exercise Translational Medicine Centre, Shanghai Centre for Systems Biomedicine Shanghai, Shanghai Jiao Tong University, Shanghai, Shanghai, China
- Department of Physical Education, Shanghai Jiao Tong University, Shanghai, Shanghai, China
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Wilhelm Bloch
- Department of Molecular and Cellular Sports Medicine, German Sport University Cologne, Cologne, Germany
| | - Moritz Schumann
- Department of Sports Medicine and Exercise Therapy, Institute of Human Movement Science and Health, Chemnitz University of Technology, Chemnitz, Germany
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Ikizler TA, Kramer HJ, Beddhu S, Chang AR, Friedman AN, Harhay MN, Jimenez EY, Kistler B, Kukla A, Larson K, Lavenburg LU, Navaneethan SD, Ortiz J, Pereira RI, Sarwer DB, Schauer PR, Zeitler EM. ASN Kidney Health Guidance on the Management of Obesity in Persons Living with Kidney Diseases. J Am Soc Nephrol 2024; 35:1574-1588. [PMID: 39292519 PMCID: PMC11543020 DOI: 10.1681/asn.0000000512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/20/2024] Open
Affiliation(s)
- T. Alp Ikizler
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Holly J. Kramer
- Division of Nephrology and Hypertension, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Srinivasan Beddhu
- Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Alex R. Chang
- Department of Population Health Sciences, Kidney Health Research Institute, Geisinger Health System, Danville, Pennsylvania
| | - Allon N. Friedman
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Meera N. Harhay
- Department of Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Elizabeth Yakes Jimenez
- College of Population Health, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Brandon Kistler
- Department of Nutrition Science, Purdue University, West Lafayette, Indiana
| | - Aleksandra Kukla
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Kristin Larson
- Roseman University College of Nursing, South Jordan, Utah
| | - LindaMarie U. Lavenburg
- Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Sankar Dass Navaneethan
- Section of Nephrology, Department of Medicine, Baylor College of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | | | | | - David B. Sarwer
- Temple University College of Public Health, Temple University, Philadelphia, Pennsylvania
| | - Philip R. Schauer
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana
| | - Evan M. Zeitler
- Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina Kidney Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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Handelsman Y, Anderson JE, Bakris GL, Ballantyne CM, Bhatt DL, Bloomgarden ZT, Bozkurt B, Budoff MJ, Butler J, Cherney DZI, DeFronzo RA, Del Prato S, Eckel RH, Filippatos G, Fonarow GC, Fonseca VA, Garvey WT, Giorgino F, Grant PJ, Green JB, Greene SJ, Groop PH, Grunberger G, Jastreboff AM, Jellinger PS, Khunti K, Klein S, Kosiborod MN, Kushner P, Leiter LA, Lepor NE, Mantzoros CS, Mathieu C, Mende CW, Michos ED, Morales J, Plutzky J, Pratley RE, Ray KK, Rossing P, Sattar N, Schwarz PEH, Standl E, Steg PG, Tokgözoğlu L, Tuomilehto J, Umpierrez GE, Valensi P, Weir MR, Wilding J, Wright EE. DCRM 2.0: Multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases. Metabolism 2024; 159:155931. [PMID: 38852020 DOI: 10.1016/j.metabol.2024.155931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 04/30/2024] [Indexed: 06/10/2024]
Abstract
The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes.
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Affiliation(s)
| | | | | | - Christie M Ballantyne
- Department of Medicine, Baylor College of Medicine, Texas Heart Institute, Houston, TX, USA
| | - Deepak L Bhatt
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, NY, New York, USA
| | - Zachary T Bloomgarden
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, NY, New York, USA
| | - Biykem Bozkurt
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | | | - Javed Butler
- University of Mississippi Medical Center, Jackson, MS, USA
| | - David Z I Cherney
- Division of Nephrology, Department of Medicine, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada
| | | | - Stefano Del Prato
- Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Robert H Eckel
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Gerasimos Filippatos
- Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece
| | | | | | | | - Francesco Giorgino
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Bari, Italy
| | | | - Jennifer B Green
- Division of Endocrinology, Metabolism, and Nutrition, Duke University School of Medicine, Durham, NC, USA
| | - Stephen J Greene
- Division of Cardiology, Duke University School of Medicine, Durham, NC, USA
| | - Per-Henrik Groop
- Department of Nephrology, University of Helsinki, Finnish Institute for Health and Helsinki University HospitalWelfare, Folkhälsan Research Center, Helsinki, Finland; Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
| | - George Grunberger
- Grunberger Diabetes Institute, Bloomfield Hills, MI, USA; Wayne State University School of Medicine, Detroit, MI, USA; Oakland University William Beaumont School of Medicine, Rochester, MI, USA; Charles University, Prague, Czech Republic
| | | | - Paul S Jellinger
- The Center for Diabetes & Endocrine Care, University of Miami Miller School of Medicine, Hollywood, FL, USA
| | | | - Samuel Klein
- Washington University School of Medicine, Saint Louis, MO, USA
| | - Mikhail N Kosiborod
- Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, MO, USA
| | | | | | - Norman E Lepor
- David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | | | - Chantal Mathieu
- Department of Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Christian W Mende
- University of California San Diego School of Medicine, La Jolla, CA, USA
| | - Erin D Michos
- Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Javier Morales
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, Advanced Internal Medicine Group, PC, East Hills, NY, USA
| | - Jorge Plutzky
- Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
| | | | | | | | | | - Peter E H Schwarz
- Department for Prevention and Care of Diabetes, Faculty of Medicine Carl Gustav Carus at the Technische Universität/TU Dresden, Dresden, Germany
| | - Eberhard Standl
- Munich Diabetes Research Group e.V. at Helmholtz Centre, Munich, Germany
| | - P Gabriel Steg
- Université Paris-Cité, Institut Universitaire de France, AP-HP, Hôpital Bichat, Cardiology, Paris, France
| | | | - Jaakko Tuomilehto
- University of Helsinki, Finnish Institute for Health and Welfare, Helsinki, Finland
| | | | - Paul Valensi
- Polyclinique d'Aubervilliers, Aubervilliers and Paris-Nord University, Paris, France
| | - Matthew R Weir
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - John Wilding
- University of Liverpool, Liverpool, United Kingdom
| | - Eugene E Wright
- Department of Medicine, Duke University Medical Center, Durham, NC, USA
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8
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Alsolami K, Hamza RZ. Orlistat and metformin combination ameliorates obesity-induced renal injury via suppressing renal oxidative stress in male rats. Toxicol Res (Camb) 2024; 13:tfae135. [PMID: 39175812 PMCID: PMC11336066 DOI: 10.1093/toxres/tfae135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 08/01/2024] [Accepted: 08/12/2024] [Indexed: 08/24/2024] Open
Abstract
BACKGROUND Orlistat (ORS) and metformin (MEF) are robustly used as well-established clinical drugs for the treatment for both obesity and the consequences of diabetes mellitus. Additionally, no study has been conducted to explore the consequence of the combination of both ORS and MEF on the kidneys of rats with obesity-induced renal injury (OBS). OBJECTIVES Therefore, the objective of the current research was designed to explore the possible ameliorative effects of either ORS and/or MEF or their combination against obesity (OBS) induced experimental renal oxidative stress. METHODS Renal oxidative stress was investigated at redox histopathological and immunohistological points in the kidney tissues. RESULTS The levels of urea, uric acid, and creatinine increased with the obesity effect; in addition, the myeloperoxidase (MPO) and xanthine oxidase (XO) activators were elevated significantly with the induction of OBS. The levels of non-enzymatic antioxidants (glutathione and thiol) declined sharply in OBS rats as compared to the normal group. CONCLUSION The data displayed that the combination of both ORS and MEF declined the obesity effects significantly by reducing the level of peroxidation (MDA), and enhancement intracellular antioxidant enzymes. These biochemical findings were supported by histopathology, immunohistochemistry, and Masson-Trichrome evaluation, which showed minor morphological changes in the kidneys of rats.
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Affiliation(s)
- Khadeejah Alsolami
- Pharmacology and Toxicology Department, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Reham Z Hamza
- Biology Department, College of Sciences, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
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9
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Bailey CJ. Metformin: Therapeutic profile in the treatment of type 2 diabetes. Diabetes Obes Metab 2024; 26 Suppl 3:3-19. [PMID: 38784991 DOI: 10.1111/dom.15663] [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: 03/31/2024] [Revised: 05/02/2024] [Accepted: 05/05/2024] [Indexed: 05/25/2024]
Abstract
Metformin (dimethyl-biguanide) can claim its origins in the use of Galega officinalis as a plant treatment for symptoms ascribed to diabetes. Since the first clinical use of metformin as a glucose-lowering agent in 1957, this medicine has emerged as a first-line pharmacological option to support lifestyle interventions in the management of type 2 diabetes (T2D). It acts through multiple cellular pathways, principally in the gut, liver and muscle, to counter insulin resistance and lower blood glucose without weight gain or risk of overt hypoglycaemia. Other effects include improvements in lipid metabolism, decreased inflammation and lower long-term cardiovascular risk. Metformin is conveniently combined with other diabetes medications, can be prescribed in prediabetes to reduce the risk of progression to T2D, and is used in some regions to assist glycaemic control in pregnancy. Consistent with its diversity of actions, established safety profile and cost-effectiveness, metformin is being assessed for further possible clinical applications. The use of metformin requires adequate renal function for drug elimination, and may cause initial gastrointestinal side effects, which can be moderated by taking with meals or using an extended-release formulation. Thus, metformin serves as a valuable therapeutic resource for use throughout the natural history of T2D.
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10
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Daka Q, Neziri B, Lindner E, Azuara Blanco A. Metformin in Glaucoma Treatment. J Glaucoma 2024; 33:387-393. [PMID: 38536124 DOI: 10.1097/ijg.0000000000002387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 03/07/2024] [Indexed: 06/01/2024]
Abstract
PRCIS Rigorous trials are essential to develop comprehensive treatment strategies that fully exploit the therapeutic potential of metformin in the treatment of glaucoma. OBJECTIVE The objective of this study was to evaluate the potentially beneficial effect of metformin on glaucoma risk factors and to investigate the underlying mechanisms. The aim is to contribute to the development of new treatment strategies for glaucoma. METHODS We searched for studies that assessed the effects of metformin on glaucoma risk factors and the associated underlying mechanisms. Our search included electronic databases such as PUBMED, EMBASE, and clinicaltrials.gov. RESULTS Unfortunately, we did not find any clinical trials that specifically investigated the impact of metformin on glaucoma. However, data from experimental studies demonstrated the capability of metformin to modulate various pathways that could contribute to neuroprotection in glaucoma. CONCLUSION In order to develop comprehensive treatment strategies that fully exploit the therapeutic potential of metformin in the treatment of glaucoma, rigorous trials are essential. These studies are necessary to demonstrate both the safety and efficacy of metformin in the context of glaucoma treatment.
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Affiliation(s)
- Qëndresë Daka
- Department of Pathophysiology, Medical Faculty, University of Prishtina, Prishtinë, Kosovo
- Department of Ophthalmology, University Clinical Centre of Kosova, Prishtinë, Kosovo
| | - Burim Neziri
- Department of Pathophysiology, Medical Faculty, University of Prishtina, Prishtinë, Kosovo
| | - Ewald Lindner
- Department of Ophthalmology, Medical University of Granz, Auenbruggerplatz, Granz, Austria
| | - Augusto Azuara Blanco
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, UK
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11
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Rhee JJ, Han J, Montez-Rath ME, Chertow GM. Comparative effectiveness of sodium-glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes and mild/moderate chronic kidney disease. Diabetes Obes Metab 2024; 26:1273-1281. [PMID: 38186297 PMCID: PMC10932840 DOI: 10.1111/dom.15427] [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: 03/10/2023] [Revised: 12/06/2023] [Accepted: 12/11/2023] [Indexed: 01/09/2024]
Abstract
AIM To determine the comparative effectiveness regarding major cardiovascular events of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). MATERIALS AND METHODS We assembled a cohort of commercially insured adult patients with T2DM in the United States (derived from Optum Clinformatics DataMart 2003-2021) who were new users of GLP-1 receptor agonists or SGLT-2 inhibitors. We compared risks of non-fatal myocardial infarction or stroke in patients with and without CKD, and further categorized by CKD stage: stages G1 or G2 [estimated glomerular filtration rate (eGFR) ≥60 ml/min] and A2 (urine albumin to creatinine ratio 30 to <300 mg/g) or A3 (urine albumin to creatinine ratio ≥300 mg/g), stage G3a (eGFR 45 to <60 ml/min/1.73 m2 ) and stage G3b (eGFR 30 to <45 ml/min/1.73 m2 ). We used proportional hazards regression after inverse probability of treatment weighting to compute hazard ratios and 95% confidence intervals. RESULTS After accounting for the probability of treatment, patients with T2DM and CKD treated with SGLT-2 inhibitors experienced a 14% lower risk of non-fatal myocardial infarction or stroke (hazard ratio 0.86, 95% confidence interval 0.78-0.94) relative to those treated with GLP-1 receptor agonists. CONCLUSIONS Recognizing the potential for residual confounding, selection bias and immortal time bias, commercially insured patients in the United States with T2DM and CKD treated with SGLT-2 inhibitors experienced significantly lower risks of non-fatal myocardial infarction or stroke relative to those treated with GLP-1 receptor agonists.
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Affiliation(s)
- Jinnie J. Rhee
- Division of Nephrology, Stanford University School of Medicine, Stanford, CA, United States
| | - Jialin Han
- Division of Nephrology, Stanford University School of Medicine, Stanford, CA, United States
| | - Maria E. Montez-Rath
- Division of Nephrology, Stanford University School of Medicine, Stanford, CA, United States
| | - Glenn M. Chertow
- Division of Nephrology, Stanford University School of Medicine, Stanford, CA, United States
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12
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Kuang W, Raven LM, Muir CA. Early post-transplant hyperglycemia and post-transplant diabetes mellitus following heart transplantation. Expert Rev Endocrinol Metab 2024; 19:129-140. [PMID: 38251642 DOI: 10.1080/17446651.2024.2307011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 01/15/2024] [Indexed: 01/23/2024]
Abstract
INTRODUCTION Heart transplantation is an important treatment for end-stage heart failure. Early post-transplant hyperglycemia (EPTH) and post-transplant diabetes mellitus (PTDM) are common following heart transplantation and are associated with increased morbidity and mortality. AREAS COVERED This review summarizes the clinical characteristics, diagnosis, and treatment of EPTH and PTDM in cardiac transplant patients, incorporating findings from non-cardiac solid organ transplant studies where relevant due to limited heart-specific research. EXPERT OPINION EPTH following heart transplantation is common yet understudied and is associated with the later development of PTDM. PTDM is associated with adverse outcomes including infection, renal dysfunction, microvascular disease, and an increased risk of re-transplantation and mortality. Risk factors for EPTH include the post-operative immunosuppression regimen, recipient and donor age, body mass index, infections, and chronic inflammation. Early insulin treatment is recommended for EPTH, whereas PTDM management is varied and includes lifestyle modification, anti-glycemic agents, and insulin. Given the emerging evidence on the transplant benefits associated with effective glucose control, and the cardioprotective potential of newer anti-glycemic agents, further focus on the management of EPTH and PTDM within heart transplant recipients is imperative.
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Affiliation(s)
- William Kuang
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW, Australia
| | - Lisa M Raven
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW, Australia
- Department of Endocrinology, St. Vincent's Hospital, Darlinghurst, NSW, Australia
| | - Christopher A Muir
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Kensington, NSW, Australia
- Department of Endocrinology, St. Vincent's Hospital, Darlinghurst, NSW, Australia
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13
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Satpathy S, Panigrahi LL, Arakha M. The Role of Selenium Nanoparticles in Addressing Diabetic Complications: A Comprehensive Study. Curr Top Med Chem 2024; 24:1327-1342. [PMID: 38561614 DOI: 10.2174/0115680266299494240326083936] [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: 12/19/2023] [Revised: 03/04/2024] [Accepted: 03/13/2024] [Indexed: 04/04/2024]
Abstract
Diabetes, as an emerging epidemic, has put forward a significant spotlight on the evolving population worldwide grounded upon the remarkable affliction of healthcare along with economical conflict. Various studies suggested that, in modern society, lack of maintenance of a healthy life style leads to the occurrence of diabetes as insulin resistant, later having a damaging effect on the pancreatic β-cells, suggesting various complications. Furthermore, diabetes management is controversial owing to different opinions based on the prevention of complications. For this purpose, nanostructured materials (NSM) like selenium nanoparticles (SeNPs) have proved their efficiency in the therapeutic management of such serious diseases. This review offers an in- -depth idea regarding the pathophysiology, diagnosis and various conventional therapeutics of type 1 and type 2 diabetes, shedding light on Diabetic Nephropathy (DN), a case study of type 1 diabetes. Moreover, this review provides an exhaustive study by highlighting the economic and healthcare burdens associated with diabetes along with the controversies associated with conventional therapeutic management and the promising role of NSM like selenium nanoparticles (SeNPs), as a novel weapon for encountering such fatal diseases.
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Affiliation(s)
- Siddharth Satpathy
- Centre for Biotechnology, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, 751003, Odisha, India
| | - Lipsa Leena Panigrahi
- Centre for Biotechnology, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, 751003, Odisha, India
| | - Manoranjan Arakha
- Centre for Biotechnology, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, 751003, Odisha, India
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14
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Scheen AJ. Clinical pharmacology of antidiabetic drugs: What can be expected of their use? Presse Med 2023; 52:104158. [PMID: 36565754 DOI: 10.1016/j.lpm.2022.104158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
The pharmacotherapy of type 2 diabetes mellitus (T2DM) has markedly evolved in the last two decades. Classical antidiabetic agents (sulphonylureas, metformin, insulin) are now in competition with new glucose-lowering medications. Alpha-glucosidase inhibitors and thiazolidinediones (glitazones) were not able to replace older agents, because of insufficient efficacy and/or poor tolerability/safety. In contrast, incretin-based therapies, both dipeptidyl peptidase-4 inhibitors (DPP-4is or gliptins, oral agents) and glucagon-like peptide-1 receptor agonists (GLP-1RAs, subcutaneous injections) are a major breakthrough in the management of T2DM. Because they are not associated with hypoglycaemia and weight gain, DPP-4is tend to replace sulphonylureas as add-on to metformin while GLP-1RAs tend to replace basal insulin therapy after failure of oral therapies. Furthermore, placebo-controlled cardiovascular outcome trials demonstrated neutrality for DPP-4is, but cardiovascular protection for GLP-1RAs in patients with T2DM at high cardiovascular risk. More recently sodium-glucose cotransporter 2 inhibitors (SGLT2is or gliflozins, oral agents) also showed cardiovascular protection, especially a reduction in hospitalization for heart failure, as well as a renal protection in patients with and without T2DM, at high cardiovascular risk, with established heart failure and/or with chronic kidney disease. Thus, GLP-1RAs and SGLT2is are now considered as preferred drugs in T2DM patients with or at high risk of atherosclerotic cardiovascular disease whereas SGLT2is are more specifically recommended in patients with or at risk of heart failure and renal (albuminuric) disease. The management of T2DM is moving from a glucocentric approach to a broader strategy focusing on all risk factors, including overweight/obesity, and to an organ-disease targeted personalized approach.
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Affiliation(s)
- André J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium; Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium.
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15
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Singh AK, Kumar P, Rajput VD, Mishra SK, Tiwari KN, Singh AK, Minkina T, Pandey AK. Phytochemicals, Antioxidant, Anti-inflammatory Studies, and Identification of Bioactive Compounds Using GC-MS of Ethanolic Novel Polyherbal Extract. Appl Biochem Biotechnol 2023:10.1007/s12010-023-04363-7. [PMID: 36701094 DOI: 10.1007/s12010-023-04363-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/10/2023] [Indexed: 01/27/2023]
Abstract
Hyperglycemia is the hallmark of diabetes, which is a collection of related metabolic disorders. Over time, diabetes can cause a variety of problems, including cardiovascular disease, nephropathy, neuropathy, and retinopathy. Ethanolic novel polyherbal extract (PHE) was prepared by mixing equal amounts of the following ingredients: Terminalia chebula Retz. (TC), Terminalia bellerica Roxb. (TB), Berberis aristata DC. (BA), Nyctanthes arbostratis L. (NA), Premna integrifolia L. (PI), and Andrographis paniculata Nees. (AP). Analysis of PHE results revealed phytochemicals like glycosides, flavonoids, alkaloids, tannins, phytosterols, and saponins. The aim of the study was to prepare an ethanolic extract of PHE using the cold maceration technique, and identify bioactive molecules from gas chromatography-mass spectrometry (GC-MS) analysis, and evaluate biological responses by using in vitro studies like antioxidant and anti-inflammatory activity. PHE was found to contain a total of 35 phytochemicals in GC-MS of which 22 bioactive compounds were obtained in good proportion. There are a few new ones, including 2-buten-1-ol, 2-ethyl-4-(2, 2, 3-trimethyl-3-cyclopenten-1-yl (17.22%), 1, 2, 5, 6-tetrahydrobenzonitrile (4.26%), 4-piperidinamine, 2, 2, 6, 6-tetramethyl-(0.07%), undecanoic acid, 5-chloro-, chloromethyl ester (0.41%), are identified. Antioxidant activity was estimated using EC50 values of 392.143 µg/ml, which were comparable to the standard value of EC50 310.513 µg/ml obtained using DPPH. Antioxidant activity was estimated with EC50 392.143 µg/ml, comparable to standard EC50 310.513 µg/ml using DPPH. In vitro anti-inflammatory potential was found with IC50 of 91.449 µg/ml, comparable to standard IC50 89.451 µg/ml for membrane stabilization and IC50 of 36.940 µg/ml, comparable to standard IC50 35.723 µg/ml for protein denaturation assays. As a result, the findings of this study show an enrichment of bioactive phytochemicals that can be used to investigate biological activity. To better understand how diabetes receptors work, in silico studies like docking could be carried out.
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Affiliation(s)
- Amit Kumar Singh
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India
| | - Pradeep Kumar
- Department of Botany, MMV, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India
| | - Vishnu D Rajput
- Academy of Biology and Biotechnology, Southern Federal University, Rostov On Don, Russia
| | - Sunil Kumar Mishra
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India.
| | - Kavindra Nath Tiwari
- Department of Botany, MMV, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India
| | - Anand Kumar Singh
- Department of Chemistry, PG College, Mariahu, VBS Purvanchal University, Jaunpur, Uttar Pradesh, 222161, India
| | - Tatiana Minkina
- Academy of Biology and Biotechnology, Southern Federal University, Rostov On Don, Russia
| | - Ajay Kumar Pandey
- Department of Kaychikitsa, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, 221005, India
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16
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Huber J, Smeikal M, Saely CH, Stingl H, Clodi M, Lechleitner M, Fasching P. [Geriatric aspects for the management of diabetes mellitus (Update 2023)]. Wien Klin Wochenschr 2023; 135:307-318. [PMID: 37101051 PMCID: PMC10133361 DOI: 10.1007/s00508-022-02124-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/09/2022] [Indexed: 04/28/2023]
Abstract
There is a high prevalence of diabetes mellitus in the elderly population of industrial countries. The present article provides recommendations for the screening, prevention and treatment of elderly diabetic patients according to current scientific evidence.
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Affiliation(s)
- Joakim Huber
- Abteilung für Innere Medizin mit Akutgeriatrie und Palliativmedizin, Franziskus Spital, Standort Landstraße, Landstraßer Hauptstraße 4a, 1030 Wien, Österreich
| | - Michael Smeikal
- Abteilung für Innere Medizin mit allgemeiner Geriatrie und Palliativmedizin, Haus der Barmherzigkeit, Wien, Österreich
| | - Christoph H. Saely
- Abteilung für Innere Medizin und Kardiologie/VIVIT-Institut, Landeskrankenhaus Feldkirch, Feldkirch, Österreich
| | - Harald Stingl
- Interne Abteilung, Landesklinikum Melk, Melk, Österreich
| | - Martin Clodi
- ICMR—Institute for Cardiovascular and Metabolic Research, Johannes Kepler Universität Linz (JKU Linz), 4040 Linz, Österreich
| | - Monika Lechleitner
- Interne Abteilung, Landeskrankenhaus Hochzirl – Natters, Hochzirl, Österreich
| | - Peter Fasching
- 5. Medizinische Abteilung mit Endokrinologie, Rheumatologie und Akutgeriatrie, Klinik Ottakring der Stadt Wien, Wien, Österreich
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17
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DeMarsilis A, Reddy N, Boutari C, Filippaios A, Sternthal E, Katsiki N, Mantzoros C. Pharmacotherapy of type 2 diabetes: An update and future directions. Metabolism 2022; 137:155332. [PMID: 36240884 DOI: 10.1016/j.metabol.2022.155332] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/06/2022]
Abstract
Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment is constantly changing as new therapies emerge and the understanding of currently available agents deepens. This review aims to provide an updated summary of the pharmacotherapeutic approach to T2D. Each class of agents is presented by mechanism of action, details of administration, side effect profile, cost, and use in certain populations including heart failure, non-alcoholic fatty liver disease, obesity, chronic kidney disease, and older individuals. We also review targets of novel therapeutic T2D agent development. Finally, we outline an up-to-date treatment approach that starts with identification of an individualized goal for glycemic control then selection, initiation, and further intensification of a personalized therapeutic plan for T2D.
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Affiliation(s)
- Antea DeMarsilis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Niyoti Reddy
- Department of Medicine, School of Medicine, Boston University, Boston, USA
| | - Chrysoula Boutari
- Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Andreas Filippaios
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Elliot Sternthal
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
| | - Niki Katsiki
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Sindos, Greece; School of Medicine, European University Cyprus, Nicosia, Cyprus.
| | - Christos Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA; Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
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18
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Metformin-Associated Lactic Acidosis in a Diabetic Patient with Normal Kidney Function and Occult Cirrhosis. Case Rep Crit Care 2022; 2022:5506744. [PMID: 36247416 PMCID: PMC9556255 DOI: 10.1155/2022/5506744] [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: 08/18/2022] [Revised: 09/24/2022] [Accepted: 09/26/2022] [Indexed: 11/05/2022] Open
Abstract
Background Lactic acidosis is a well-known complication of metformin accumulation in diabetic patients with kidney failure. However, it is not usual to raise the diagnosis of metformin-associated lactic acidosis when patients have normal kidney function. The causes of metformin-induced high lactate include the accumulation of normal doses of metformin in chronic kidney disease, an overdose of this drug without kidney failure, or an increase in lactate production due to the inhibition of liver gluconeogenesis. Case Presentation. We report the case of a 61-year-old diabetic man who was brought to the emergency room in a comatose state. His family reported abdominal pain with diarrhea in the last two days. He was found to have severe lactic acidosis with normal serum creatinine. He was on a regular dose of metformin, and his family denied any other medical history or any alcohol abuse. He showed no signs of infection, his liver enzymes were slightly elevated, and he had severe anemia. His hemodynamics deteriorated quickly within hours, and an abdominal computed tomography scan revealed no abnormalities. He underwent a laparotomy that ruled out mesenteric ischemia and revealed an abnormal liver. The liver biopsy later confirmed the diagnosis of cirrhosis. Conclusions We discuss here the probable causes of severe lactic acidosis and the role of metformin in exacerbating this acid-base disturbance in cirrhotic patients. Future research is needed to determine whether these patients might benefit from dialysis.
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19
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Blonde L, Umpierrez GE, Reddy SS, McGill JB, Berga SL, Bush M, Chandrasekaran S, DeFronzo RA, Einhorn D, Galindo RJ, Gardner TW, Garg R, Garvey WT, Hirsch IB, Hurley DL, Izuora K, Kosiborod M, Olson D, Patel SB, Pop-Busui R, Sadhu AR, Samson SL, Stec C, Tamborlane WV, Tuttle KR, Twining C, Vella A, Vellanki P, Weber SL. American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. Endocr Pract 2022; 28:923-1049. [PMID: 35963508 PMCID: PMC10200071 DOI: 10.1016/j.eprac.2022.08.002] [Citation(s) in RCA: 234] [Impact Index Per Article: 78.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers. METHODS The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RESULTS This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes. CONCLUSIONS This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.
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Affiliation(s)
| | | | - S Sethu Reddy
- Central Michigan University, Mount Pleasant, Michigan
| | | | | | | | | | | | - Daniel Einhorn
- Scripps Whittier Diabetes Institute, La Jolla, California
| | | | | | - Rajesh Garg
- Lundquist Institute/Harbor-UCLA Medical Center, Torrance, California
| | | | | | | | | | | | - Darin Olson
- Colorado Mountain Medical, LLC, Avon, Colorado
| | | | | | - Archana R Sadhu
- Houston Methodist; Weill Cornell Medicine; Texas A&M College of Medicine; Houston, Texas
| | | | - Carla Stec
- American Association of Clinical Endocrinology, Jacksonville, Florida
| | | | - Katherine R Tuttle
- University of Washington and Providence Health Care, Seattle and Spokane, Washington
| | | | | | | | - Sandra L Weber
- University of South Carolina School of Medicine-Greenville, Prisma Health System, Greenville, South Carolina
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20
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O'Brien MJ, Vargas MC, Lopez A, Feliciano Y, Gregory DL, Carcamo P, Mohr L, Mohanty N, Padilla R, Ackermann RT, Persell SD, Feinglass J. Development of a novel clinical decision support tool for diabetes prevention and feasibility of its implementation in primary care. Prev Med Rep 2022; 29:101979. [PMID: 36161117 PMCID: PMC9501986 DOI: 10.1016/j.pmedr.2022.101979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 08/31/2022] [Accepted: 09/02/2022] [Indexed: 11/12/2022] Open
Abstract
Clinical decision support may represent a strategy for promoting diabetes prevention in primary care. We developed a novel clinical decision support tool with input from primary care providers. This clinician-facing tool was associated with improvements in processes of prediabetes care. Exploratory analyses found small, but nonsignificant weight loss associated with its use. Prediabetes impacts 88 million U.S. adults, yet uptake of evidence-based treatment with intensive lifestyle interventions and metformin remains exceedingly low. After incorporating feedback from 15 primary care providers collected during semi-structured interviews, we developed a novel Prediabetes Clinical Decision Support (PreDM CDS) from August 2019 to February 2020. This tool included order options enabling prediabetes management in a single location within the electronic health record. We conducted a retrospective observational study examining the feasibility of implementing this tool at Erie Family Health Centers, a large community health center, examining its use and related outcomes among patients for whom it was used vs not. Overall, 7,424 eligible patients were seen during the implementation period (February 2020 to August 2021), and the PreDM CDS was used for 108 (1.5 %). Using the PreDM CDS was associated with higher rates of hemoglobin A1c orders (70.4 % vs 22.2 %; p < 0.001), lifestyle counseling (38.0 % vs 7.8 %; p < 0.001), and metformin prescription orders (5.6 % vs 2.6 %; p = 0.06). Exploratory analyses revealed small, nonsignificant weight loss among patients for whom the PreDM CDS was used. This study demonstrates the feasibility of developing and implementing the PreDM CDS in primary care. Its low use was likely related to not imposing an interruptive ‘pop-up’ alert, as well as major changes in workflows and clinical priorities during the Covid-19 pandemic. Use of the tool was associated with improved process outcomes. Future efforts with the PreDM CDS should follow standard CDS implementation processes that were not possible due to the Covid-19 pandemic.
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Affiliation(s)
- Matthew J O'Brien
- Division of General Internal Medicine and Geriatrics, Department of Medicine, Northwestern University Feinberg School of Medicine. 750 N. Lakeshore Drive, 10 Floor, Chicago, IL 60611, United States.,Institute of Public Health and Medicine, Northwestern University Feinberg School of Medicine. 750 N. Lakeshore Drive, 6 Floor, Chicago, IL 60611, United States.,Department of Preventive Medicine, Northwestern University Feinberg School of Medicine. 680 N. Lakeshore Drive, 14 Floor, Chicago, IL 60611, United States
| | - Maria C Vargas
- Division of General Internal Medicine and Geriatrics, Department of Medicine, Northwestern University Feinberg School of Medicine. 750 N. Lakeshore Drive, 10 Floor, Chicago, IL 60611, United States.,Institute of Public Health and Medicine, Northwestern University Feinberg School of Medicine. 750 N. Lakeshore Drive, 6 Floor, Chicago, IL 60611, United States
| | - Azucena Lopez
- Division of General Internal Medicine and Geriatrics, Department of Medicine, Northwestern University Feinberg School of Medicine. 750 N. Lakeshore Drive, 10 Floor, Chicago, IL 60611, United States.,Institute of Public Health and Medicine, Northwestern University Feinberg School of Medicine. 750 N. Lakeshore Drive, 6 Floor, Chicago, IL 60611, United States
| | - Yury Feliciano
- Division of General Internal Medicine and Geriatrics, Department of Medicine, Northwestern University Feinberg School of Medicine. 750 N. Lakeshore Drive, 10 Floor, Chicago, IL 60611, United States.,Institute of Public Health and Medicine, Northwestern University Feinberg School of Medicine. 750 N. Lakeshore Drive, 6 Floor, Chicago, IL 60611, United States
| | - Dyanna L Gregory
- Division of General Internal Medicine and Geriatrics, Department of Medicine, Northwestern University Feinberg School of Medicine. 750 N. Lakeshore Drive, 10 Floor, Chicago, IL 60611, United States
| | - Paula Carcamo
- Erie Family Health Centers. 1701 W. Superior Street, Chicago, IL 60622, United States
| | - Loretta Mohr
- Erie Family Health Centers. 1701 W. Superior Street, Chicago, IL 60622, United States
| | - Nivedita Mohanty
- Erie Family Health Centers. 1701 W. Superior Street, Chicago, IL 60622, United States.,AllianceChicago. 225 W. Illinois Street, 5 Floor, Chicago, IL 60654, United States
| | - Roxane Padilla
- AllianceChicago. 225 W. Illinois Street, 5 Floor, Chicago, IL 60654, United States
| | - Ronald T Ackermann
- Division of General Internal Medicine and Geriatrics, Department of Medicine, Northwestern University Feinberg School of Medicine. 750 N. Lakeshore Drive, 10 Floor, Chicago, IL 60611, United States.,Institute of Public Health and Medicine, Northwestern University Feinberg School of Medicine. 750 N. Lakeshore Drive, 6 Floor, Chicago, IL 60611, United States
| | - Stephen D Persell
- Division of General Internal Medicine and Geriatrics, Department of Medicine, Northwestern University Feinberg School of Medicine. 750 N. Lakeshore Drive, 10 Floor, Chicago, IL 60611, United States.,Institute of Public Health and Medicine, Northwestern University Feinberg School of Medicine. 750 N. Lakeshore Drive, 6 Floor, Chicago, IL 60611, United States
| | - Joseph Feinglass
- Division of General Internal Medicine and Geriatrics, Department of Medicine, Northwestern University Feinberg School of Medicine. 750 N. Lakeshore Drive, 10 Floor, Chicago, IL 60611, United States.,Institute of Public Health and Medicine, Northwestern University Feinberg School of Medicine. 750 N. Lakeshore Drive, 6 Floor, Chicago, IL 60611, United States
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21
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Sun P, Huang R, Qin Z, Liu F. Influence of Tangeretin on the Exponential Regression of Inflammation and Oxidative Stress in Streptozotocin-Induced Diabetic Nephropathy. Appl Biochem Biotechnol 2022; 194:3914-3929. [PMID: 35567707 DOI: 10.1007/s12010-022-03920-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2022] [Indexed: 01/08/2023]
Abstract
Diabetes is an amalgamation of metabolic disorders marked by hyperglycemia. Over time diabetes brings up several other complications with it like cardiovascular disease, retinopathy, neuropathy, and nephropathy. among which diabetic nephropathy (DN) is the one we are concerned about in the present study. Diabetes management requires following a healthy lifestyle with proper medication. Most of the anti-diabetic drugs available at present come with adverse side effects. Nature has provided us with several components that are anti-diabetic in nature which has fewer or no side effects and tangeretin is one among them. Tangeretin is a natural flavonoid abundantly present in orange peel and tangerines. Our study is designed to evaluate tangeretin, as an anti-diabetic medication especially for patients suffering from diabetic nephropathy. The procured healthy rats were first divided into four groups: the group I was maintained as healthy control and the others were subjected to the induction of diabetes by i.p. injection of streptozotocin (STZ) at the concentration of 55mg/kg b.wt .Then, the diabetic rats were further divided into three groups: group II was used as the diabetic control rats and the group III and group IV were administered with tangeretin (25mg/kg b.wt) and positive control drug metformin (150mg/kg b.wt) for 8 weeks. The body weight, blood glucose, and serum insulin levels were estimated at week 0 and week 8. Reactive oxygen species (ROS) inhibitory effect, antioxidant, antilipidemic, nephroprotective, and anti-inflammatory effects of tangeretin on the diabetic-induced rats were evaluated at the end of week 8 in addition to the histopathological assessment of the sections of the kidneys of the experimental rats. All the test results concluded that tangeretin was able to significantly decelerate the progression of DN in STZ-induced diabetic rats.
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Affiliation(s)
- Pei Sun
- Department of Endocrinology, Central Hospital Affiliated to Shandong First Medical University, No. 105, Jiefang Road, Jinan City, Shandong, 250013, China
| | - Ran Huang
- Department of Kidney Disease Unit & Dialysis, Central Hospital Affiliated to Shandong First Medical University, No. 105, Jiefang Road, Jinan City, Shandong, 250013, China
| | - Zifu Qin
- Department of Health, Vertigo Examination Room, Central Hospital Affiliated to Shandong First Medical University, No. 105, Jiefang Road, Jinan City, Shandong, 250013, China
| | - Fang Liu
- Department of Kidney Disease Unit & Dialysis, Central Hospital Affiliated to Shandong First Medical University, No. 105, Jiefang Road, Jinan City, Shandong, 250013, China.
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22
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Amin SV, Khanna S, Parvar SP, Shaw LT, Dao D, Hariprasad SM, Skondra D. Metformin and retinal diseases in preclinical and clinical studies: Insights and review of literature. Exp Biol Med (Maywood) 2022; 247:317-329. [PMID: 35068220 PMCID: PMC8899338 DOI: 10.1177/15353702211069986] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Metformin is one of the most prescribed drugs in the world giving potential health benefits beyond that of type 2 diabetes (T2DM). Emerging evidence suggests that it may have protective effects for retinal/posterior segment diseases including diabetic retinopathy (DR), age-related macular degeneration (AMD), inherited retinal degeneration such as retinitis pigmentosa (RP), primary open angle glaucoma (POAG), retinal vein occlusion (RVO), and uveitis. Metformin exerts potent anti-inflammatory, antiangiogenic, and antioxidative effects on the retina in response to pathologic stressors. In this review, we highlight the broad mechanism of action of metformin through key preclinical studies on animal models and cell lines used to simulate human retinal disease. We then explore the sparse but promising retrospective clinical data on metformin's potential protective role in DR, AMD, POAG, and uveitis. Prospective clinical data is needed to clarify metformin's role in management of posterior segment disorders. However, given metformin's proven broad biochemical effects, favorable safety profile, relatively low cost, and promising data to date, it may represent a new therapeutic preventive and strategy for retinal diseases.
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Affiliation(s)
- Shivam V Amin
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL 60637, USA
| | - Saira Khanna
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL 60637, USA
| | - Seyedeh P Parvar
- Islamic Azad University Tehran Faculty of Medicine, Tehran QCGM+X9, Tehran Province, Iran
| | - Lincoln T Shaw
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL 60637, USA
| | - David Dao
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL 60637, USA
| | - Seenu M Hariprasad
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL 60637, USA
| | - Dimitra Skondra
- Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL 60637, USA
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23
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Handelsman Y, Anderson JE, Bakris GL, Ballantyne CM, Beckman JA, Bhatt DL, Bloomgarden ZT, Bozkurt B, Budoff MJ, Butler J, Dagogo-Jack S, de Boer IH, DeFronzo RA, Eckel RH, Einhorn D, Fonseca VA, Green JB, Grunberger G, Guerin C, Inzucchi SE, Jellinger PS, Kosiborod MN, Kushner P, Lepor N, Mende CW, Michos ED, Plutzky J, Taub PR, Umpierrez GE, Vaduganathan M, Weir MR. DCRM Multispecialty Practice Recommendations for the management of diabetes, cardiorenal, and metabolic diseases. J Diabetes Complications 2022; 36:108101. [PMID: 34922811 PMCID: PMC9803322 DOI: 10.1016/j.jdiacomp.2021.108101] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 11/27/2021] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF)-along with their associated risk factors-have overlapping etiologies, and two or more of these conditions frequently occur in the same patient. Many recent cardiovascular outcome trials (CVOTs) have demonstrated the benefits of agents originally developed to control T2D, ASCVD, or CKD risk factors, and these agents have transcended their primary indications to confer benefits across a range of conditions. This evolution in CVOT evidence calls for practice recommendations that are not constrained by a single discipline to help clinicians manage patients with complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. The ultimate goal for these recommendations is to be comprehensive yet succinct and easy to follow by the nonexpert-whether a specialist or a primary care clinician. To meet this need, we formed a volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM Practice Recommendations, a multispecialty consensus on the comprehensive management of the patient with complicated metabolic disease. The task force recommendations are based on strong evidence and incorporate practical guidance that is clinically relevant and simple to implement, with the aim of improving outcomes in patients with DCRM. The recommendations are presented as 18 separate graphics covering lifestyle therapy, patient self-management education, technology for DCRM management, prediabetes, cognitive dysfunction, vaccinations, clinical tests, lipids, hypertension, anticoagulation and antiplatelet therapy, antihyperglycemic therapy, hypoglycemia, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), ASCVD, HF, CKD, and comorbid HF and CKD, as well as a graphical summary of medications used for DCRM.
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Affiliation(s)
| | | | | | | | | | - Deepak L Bhatt
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | | | | | | | - Javed Butler
- University of Mississippi Medical Center, Jackson, MS, USA
| | | | | | | | - Robert H Eckel
- University of Colorado Anschutz Medical Campus, Denver, CO, USA
| | - Daniel Einhorn
- Scripps Whittier Institute for Diabetes, San Diego, CA, USA
| | | | | | - George Grunberger
- Grunberger Diabetes Institute, Bloomfield Hills, MI, USA, Wayne State University School of Medicine, Detroit, MI, USA, Oakland University William Beaumont School of Medicine, Rochester, MI, USA, Charles University, Prague, Czech Republic
| | - Chris Guerin
- University of California San Diego School of Medicine, San Diego, CA, USA
| | | | - Paul S Jellinger
- The Center for Diabetes & Endocrine Care, University of Miami Miller School of Medicine, Hollywood, FL, USA
| | - Mikhail N Kosiborod
- Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, MO, USA
| | | | - Norman Lepor
- David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | - Christian W Mende
- University of California San Diego School of Medicine, San Diego, CA, USA
| | - Erin D Michos
- Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jorge Plutzky
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Pam R Taub
- University of California San Diego School of Medicine, San Diego, CA, USA
| | | | | | - Matthew R Weir
- University of Maryland School of Medicine, Baltimore, MD, USA
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24
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Kushner PR, Cavender MA, Mende CW. Role of Primary Care Clinicians in the Management of Patients With Type 2 Diabetes and Cardiorenal Diseases. Clin Diabetes 2022; 40:401-412. [PMID: 36381309 PMCID: PMC9606551 DOI: 10.2337/cd21-0119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Individuals with type 2 diabetes are at increased risk of both renal and cardiovascular events. The convergence of type 2 diabetes, chronic kidney disease, and cardiovascular disease, including heart failure, requires management by a multidisciplinary health care team. Primary care clinicians are likely to be the first and most frequent point of contact for individuals with type 2 diabetes who are at high risk of cardiorenal disease and therefore play a pivotal role in early diagnosis, establishment of effective treatment strategies, and coordination of care. This article presents a clinical perspective with multidisciplinary collaboration on a patient case representative of those seen in routine clinical practice. The authors assess reasons why patients may not receive evidence-based care and identify opportunities to initiate therapies that reduce cardiovascular and renal events in the primary care setting.
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Affiliation(s)
- Pamela R. Kushner
- University of California, Irvine, CA
- Corresponding author: Pamela R. Kushner,
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25
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Berberine and lycopene as alternative or add-on therapy to metformin and statins, a review. Eur J Pharmacol 2021; 913:174590. [PMID: 34801530 DOI: 10.1016/j.ejphar.2021.174590] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 10/19/2021] [Accepted: 10/19/2021] [Indexed: 12/27/2022]
Abstract
Nutraceuticals are principally extracted from natural products that are frequently safe and well-tolerated. Lycopene and berberine are natural plants with a wide range of beneficial effects including protective activities against metabolic disorders such as diabetes and cardiovascular diseases. These compounds might be considered technically more as a drug than a nutraceutical and could be prescribed as a product. However, further studies are needed to understand if these supplements could affect metabolic syndrome outcomes. Even if nutraceuticals exert a prophylactic activity within the body, their bioactivity and bioavailability have high interindividual variation, and precise assessment of biological function of these bioactive compounds in randomized clinical trials is critical. However, these reports must be interpreted with more considerations due to the low quality of the trials. The aim of this paper is to bring evidence about the management of cardiovascular diseases and diabetes through the use of nutraceuticals with particular attention to lycopene and berberine effectiveness.
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26
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Tsakiridis EE, Broadfield L, Marcinko K, Biziotis OD, Ali A, Mekhaeil B, Ahmadi E, Singh K, Mesci A, Zacharidis PG, Anagnostopoulos AE, Berg T, Muti P, Steinberg GR, Tsakiridis T. Combined metformin-salicylate treatment provides improved anti-tumor activity and enhanced radiotherapy response in prostate cancer; drug synergy at clinically relevant doses. Transl Oncol 2021; 14:101209. [PMID: 34479029 PMCID: PMC8411238 DOI: 10.1016/j.tranon.2021.101209] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 08/03/2021] [Accepted: 08/18/2021] [Indexed: 11/05/2022] Open
Abstract
Combined metformin + salicylate treatment has improved anti-tumor efficacy in prostate cancer. At clinically achievable doses, it induces increased metabolic stress and sensitizes tumors to radiation. Metformin + salicylate blocks pathways of de novo lipogenesis and protein synthesis. In combination with radiation suppresses HIF1a and DNA replication. This work supports clinical investigation of metformin + salicylate in combination with radiotherapy. Background There is need for well-tolerated therapies for prostate cancer (PrCa) secondary prevention and to improve response to radiotherapy (RT). The anti-diabetic agent metformin (MET) and the aspirin metabolite salicylate (SAL) are shown to activate AMP-activated protein kinase (AMPK), suppress de novo lipogenesis (DNL), the mammalian target of rapamycin (mTOR) pathway and reduce PrCa proliferation in-vitro. The purpose of this study was to examine whether combined MET+SAL treatment could provide enhanced PrCa tumor suppression and improve response to RT. Methods Androgen-sensitive (22RV1) and resistant (PC3, DU-145) PrCa cells and PC3 xenografts were used to examine whether combined treatment with MET+SAL can provide improved anti-tumor activity compared to each agent alone in non-irradiated and irradiated PrCa cells and tumors. Mechanisms of action were investigated with analysis of signaling events, mitochondria respiration and DNL activity assays. Results We observed that PrCa cells are resistant to clinically relevant doses of MET. Combined MET + SAL treatment provides synergistic anti-proliferative activity at clinically relevant doses and enhances the anti-proliferative effects of RT. This was associated with suppression of oxygen consumption rate (OCR), activation of AMPK, suppression of acetyl-CoA carboxylase (ACC)-DNL and mTOR-p70s6k/4EBP1 and HIF1α pathways. MET + SAL reduced tumor growth in non-irradiated tumors and enhanced the effects of RT. Conclusion MET+SAL treatment suppresses PrCa cell proliferation and tumor growth and enhances responses to RT at clinically relevant doses. Since MET and SAL are safe, widely-used and inexpensive agents, these data support the investigation of MET+SAL in PrCa clinical trials alone and in combination with RT.
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Affiliation(s)
- Evangelia E Tsakiridis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Lindsay Broadfield
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Katarina Marcinko
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Olga-Demetra Biziotis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Amr Ali
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Bassem Mekhaeil
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Elham Ahmadi
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Kanwaldeep Singh
- Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Aruz Mesci
- Department of Radiation Oncology, Juravinski Cancer Center, 699 Concession Street, Hamilton, Ontario L8V 5C2, Canada
| | - Panayiotis G Zacharidis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Alexander E Anagnostopoulos
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Tobias Berg
- Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Paola Muti
- Department of Oncology, McMaster University, Hamilton, Ontario, Canada
| | - Gregory R Steinberg
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Theodoros Tsakiridis
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada; Department of Oncology, McMaster University, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Radiation Oncology, Juravinski Cancer Center, 699 Concession Street, Hamilton, Ontario L8V 5C2, Canada.
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27
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Zhou G, Cui J, Xie S, Wan H, Luo Y, Guo G. Vitexin, a fenugreek glycoside, ameliorated obesity-induced diabetic nephropathy via modulation of NF-κB/IkBα and AMPK/ACC pathways in mice. Biosci Biotechnol Biochem 2021; 85:1183-1193. [PMID: 33704405 DOI: 10.1093/bbb/zbab012] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 01/12/2021] [Indexed: 12/14/2022]
Abstract
Obesity is one of the most critical risk factors for diabetes mellitus and plays a significant role in diabetic nephropathy (DN). The present investigation aimed to evaluate the possible mechanism of action of vitexin on obesity-induced DN in a high-fat diet (HFD)-fed experimental C57BL/6 mice model. Obesity was induced in male C57BL/6 mice by chronic administration of HFD, and mice were concomitantly treated with vitexin (15, 30, and 60 mg/kg, p.o.). HFD-induced increased renal oxido-nitrosative stress and proinflammatory cytokine levels were significantly inhibited by vitexin. The Western blot analysis suggested that alteration in renal NF-κB, IκBα, nephrin, AMPK, and ACC phosphorylation levels was effectively restored by vitexin treatment. Histological aberration induced in renal tissue after chronic administration of HFD was also reduced by vitexin. In conclusion, vitexin suppressed the progression of obesity-induced DN via modulation of NF-κB/IkBα and AMPK/ACC pathways in an experimental model of HFD-induced DN in C57BL/6J mice.
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Affiliation(s)
- Guangju Zhou
- Department of Endocrinology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Jiale Cui
- Department of Endocrinology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Suhua Xie
- Department of Endocrinology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Haiyan Wan
- Department of Anesthesiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Yan Luo
- Department of Rehabilitation, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Gang Guo
- Department of Talent Highland, The First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, China
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28
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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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29
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Undercover Toxic Ménage à Trois of Amylin, Copper (II) and Metformin in Human Embryonic Kidney Cells. Pharmaceutics 2021; 13:pharmaceutics13060830. [PMID: 34204936 PMCID: PMC8229594 DOI: 10.3390/pharmaceutics13060830] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 12/14/2022] Open
Abstract
In recent decades, type 2 diabetes complications have been correlated with amylin aggregation, copper homeostasis and metformin side effects. However, each factor was analyzed separately, and only in some rare cases copper/amylin or copper/metformin complexes were considered. We demonstrate for the first time that binary metformin/amylin and tertiary copper (II)/amylin/metformin complexes of high cellular toxicity are formed and lead to the formation of aggregated multi-level lamellar structures on the cell membrane. Considering the increased concentration of amylin, copper (II) and metformin in kidneys of T2DM patients, our findings on the toxicity of amylin and its adducts may be correlated with diabetic nephropathy development.
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30
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Abdel Monem MS, Farid SF, Abbassi MM, Youssry I, Andraues NG, Hassany M, Selim YMM, El-Sayed MH. The potential hepatoprotective effect of metformin in hepatitis C virus-infected adolescent patients with beta thalassemia major: Randomised clinical trial. Int J Clin Pract 2021; 75:e14104. [PMID: 33617679 DOI: 10.1111/ijcp.14104] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 02/18/2021] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Iron overload-induced oxidative stress and transfusion-acquired hepatitis C virus (HCV) infection are the main reasons of liver damage in beta thalassemia major (β-TM). OBJECTIVES Based on metformin's hepatic benefits in nondiabetic populations, the study aims to investigate the safety and the potential hepatoprotective effect of metformin in HCV-infected β-TM adolescent patients. METHODS This was a prospective, randomised, parallel, controlled, open-label study in which 60 HCV-infected β-TM adolescent patients aged 11 to 18 years and receiving no antiviral therapy were selected and randomly assigned to treatment or control group in 1:1 allocation. Both groups were receiving β-TM standard-of-care regimen, whereas metformin (500 mg, twice daily) was added to the treatment group's regimen only. Patients were prospectively followed up for 6 months with assessment of liver biochemical profile, oxidative stress markers, liver fibrosis, clinical symptom improvement and metformin's adverse effects. RESULTS Aspartate aminotransferase serum level decreased significantly over time in the treatment group only (P = .013). However, improvement was not clinically significant and did not attain normality. Change in total antioxidant capacity and malondialdehyde serum levels indicated significantly improved oxidative stress status in the treatment group versus significant deterioration in the control group (P < .001). Fibrosis grade improvement was observed in 14 patients in the treatment group versus one improved case in the control group. CONCLUSION The use of metformin in HCV-infected β-TM adolescent patients as an adjuvant antioxidant hepatoprotective agent is promising and can improve liver damage.
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Affiliation(s)
- Mona S Abdel Monem
- Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Samar F Farid
- Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Maggie M Abbassi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Ilham Youssry
- Pediatric Hematology Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Nevine G Andraues
- Department of Pediatrics and Pediatric Hematology/Oncology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Mohamed Hassany
- National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Yasmeen M M Selim
- Pediatric Hematology Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Manal H El-Sayed
- Department of Pediatrics and Pediatric Hematology/Oncology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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31
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Monteiro C, Silvestre S, Duarte AP, Alves G. Assessment of suspected adverse drug reactions in elderly patients with diabetes mellitus based on a Portuguese spontaneous reporting database: analysis of reporting from 2008 to 2018. Expert Opin Drug Saf 2021; 20:845-853. [PMID: 33962523 DOI: 10.1080/14740338.2021.1928072] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
BACKGROUND Age is one of the most important risk factors in the development of diabetes mellitus and certain drug classes indicated for this condition may be associated with clinically important adverse drug reactions (ADRs). The aim of this study was to analyze the suspected ADRs in older patients with diabetes mellitus, reported to the Portuguese Pharmacovigilance System from 2008 to 2018. RESEARCH DESIGN AND METHODS A retrospective analysis of suspected ADRs reports was performed, involving patients aged ≥65 years. RESULTS Of a total of 751 reports collected, 439 were considered serious, 199 led to hospitalization and in 19 of them occurred a fatal outcome. Most of them were observed in females (n = 393) and involved patients belonging mainly to the age group 65-74 years (n = 405). Taking into account a total of 2134 suspected ADRs, the most frequent were hypoglycemia (2.67%) and lactic acidosis (2.62%). The drugs specifically indicated for glycemic control were the most frequently involved in ADRs. CONCLUSIONS Most of the ADRs were reported as serious and were mainly associated to drugs in diabetes mellitus. In addition, the majority of them, such as hypoglycemia, are preventable, highlighting the importance to identify possible factors that determine this occurrence, especially in the elderly.
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Affiliation(s)
- Cristina Monteiro
- UFBI - Pharmacovigilance Unit of Beira Interior, University of Beira Interior, Covilhã, Portugal
| | - Samuel Silvestre
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Ana Paula Duarte
- UFBI - Pharmacovigilance Unit of Beira Interior, University of Beira Interior, Covilhã, Portugal.,CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Gilberto Alves
- UFBI - Pharmacovigilance Unit of Beira Interior, University of Beira Interior, Covilhã, Portugal.,CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.,ESALD-IPCB - Dr. Lopes Dias School of Health, Polytechnic Institute of Castelo Branco, Castelo Branco, Portugal
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Scheen AJ. Careful use to minimize adverse events of oral antidiabetic medications in the elderly. Expert Opin Pharmacother 2021; 22:2149-2165. [PMID: 33823723 DOI: 10.1080/14656566.2021.1912735] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION An increasing number of older patients has type 2 diabetes treated with different oral antidiabetic agents whose safety may raise concern considering some particularities of a heterogeneous elderly population. AREAS COVERED This article discusses some characteristics of older patients that could increase the risk of adverse events, with a focus on hypoglycemia. It describes the most frequent and/or severe complications reported in the elderly in both randomized controlled trials and observational studies with metformin, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors (gliptins) and sodium-glucose cotransporter type 2 inhibitors (gliflozins). EXPERT OPINION Old patients may present comorbidities (renal impairment, vascular disease, heart failure, risk of dehydration, osteoporosis, cognitive dysfunction) that could increase the risk of severe adverse events. Sulfonylureas (and meglitinides) induce hypoglycemia, which may be associated with falls/fractures and cardiovascular events. Medications lacking hypoglycemia should be preferred. Gliptins appear to have the best tolerance/safety profile whereas gliflozins exert a cardiorenal protection. However, data are lacking in very old or frailty old patients so that caution and appropriate supervision of such patients are required. Taking advantage of a large choice of pharmacotherapies, personalized treatment is recommended based upon both drug safety profiles and old patient individual characteristics.
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Affiliation(s)
- André J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.,Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium
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Song A, Zhang C, Meng X. Mechanism and application of metformin in kidney diseases: An update. Biomed Pharmacother 2021; 138:111454. [PMID: 33714781 DOI: 10.1016/j.biopha.2021.111454] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/26/2021] [Accepted: 02/27/2021] [Indexed: 01/08/2023] Open
Abstract
Metformin is an oral antihyperglycemic drug widely used to treat type 2 diabetes mellitus (T2DM), acting via indirect activation of 5' Adenosine monophosphate-activated Protein Kinase (AMPK). Beyond the anti-diabetic effect, accumulative pieces of evidence have revealed that metformin also everts a beneficial effect in diverse kidney diseases. In various acute kidney diseases (AKI) animal models, metformin protects renal tubular cells from inflammation, apoptosis, reactive oxygen stress (ROS), endoplasmic reticulum (ER) stress, epithelial-mesenchymal transition (EMT) via AMPK activation. In diabetic kidney disease (DKD), metformin also alleviates podocyte loss, mesangial cells apoptosis, and tubular cells senescence through AMPK-mediated signaling pathways. Besides, metformin inhibits cystic fibrosis transmembrane conductance regulator (CFTR)-mediated fluids secretion and the mammalian target of rapamycin (mTOR)-involved cyst formation negatively regulated by AMPK in autosomal dominant polycystic kidney disease (APDKD). Furthermore, metformin also contributes to the alleviation of urolithiasis and renal cell carcinoma (RCC). As the common pathway for chronic kidney disease (CKD) progressing towards end-stage renal disease (ESRD), renal fibrosis is ameliorated by metformin, to a great extent dependent on AMPK activation. However, clinical data are not always consistent with preclinical data, some clinical investigations showed the unmeaningful even detrimental effect of metformin on T2DM patients with kidney diseases. Most importantly, metformin-associated lactic acidosis (MALA) is a vital issue restricting the application of metformin. Thus, we conclude the application of metformin in kidney diseases and uncover the underlying molecular mechanisms in this review.
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Affiliation(s)
- Anni Song
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xianfang Meng
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Giaccari A, Solini A, Frontoni S, Del Prato S. Metformin Benefits: Another Example for Alternative Energy Substrate Mechanism? Diabetes Care 2021; 44:647-654. [PMID: 33608326 PMCID: PMC7896249 DOI: 10.2337/dc20-1964] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 12/03/2020] [Indexed: 02/03/2023]
Abstract
Since the UK Prospective Diabetes Study (UKPDS), metformin has been considered the first-line medication for patients with newly diagnosed type 2 diabetes. Though direct evidence from specific trials is still lacking, several studies have suggested that metformin may protect from diabetes- and nondiabetes-related comorbidities, including cardiovascular, renal, neurological, and neoplastic diseases. In the past few decades, several mechanisms of action have been proposed to explain metformin's protective effects, none being final. It is certain, however, that metformin increases lactate production, concentration, and, possibly, oxidation. Once considered a mere waste product of exercising skeletal muscle or anaerobiosis, lactate is now known to act as a major energy shuttle, redistributed from production sites to where it is needed. Through the direct uptake and oxidation of lactate produced elsewhere, all end organs can be rapidly supplied with fundamental energy, skipping glycolysis and its possible byproducts. Increased lactate production (and consequent oxidation) could therefore be considered a positive mechanism of action of metformin, except when, under specific circumstances, metformin and lactate become excessive, increasing the risk of lactic acidosis. We are proposing that, rather than considering metformin-induced lactate production as dangerous, it could be considered a mechanism through which metformin exerts its possible protective effect on the heart, kidneys, and brain and, to some extent, its antineoplastic action.
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Affiliation(s)
- Andrea Giaccari
- Center for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Anna Solini
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy
| | - Simona Frontoni
- Unit of Endocrinology, Diabetes and Metabolism, San Giovanni Calibita Fatebenefratelli Hospital, Rome, Italy
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Stefano Del Prato
- Section of Metabolic Diseases and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Nam YH, Brensinger CM, Bilker WB, Leonard CE, Hennessy S. Investigation of Concomitant Use of Alzheimer's Disease Drugs with Sulfonylureas and Serious Hypoglycemia. Epidemiology 2021; 32:e3-e5. [PMID: 33002962 PMCID: PMC7708459 DOI: 10.1097/ede.0000000000001263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Young Hee Nam
- Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA
| | - Colleen M Brensinger
- Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA,
| | - Warren B Bilker
- Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA,
| | - Charles E Leonard
- Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA,
| | - Sean Hennessy
- Center for Pharmacoepidemiology Research and Training, Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA,
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Qiu X, Xu Q, Xu T, Wan P, Sheng Z, Han Y, Yao L. Metformin alleviates β-glycerophosphate-induced calcification of vascular smooth muscle cells via AMPK/mTOR-activated autophagy. Exp Ther Med 2020; 21:58. [PMID: 33365058 PMCID: PMC7716633 DOI: 10.3892/etm.2020.9490] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 09/11/2020] [Indexed: 12/20/2022] Open
Abstract
The aim of the present study was to investigate the effect of metformin on β-glycerophosphate-induced calcification of vascular smooth muscle cells (VSMCs) and the possible mechanisms underlying this. Using an established VSMC calcification model, VSMCs were first treated with β-glycerophosphate, before metformin, 3-methyladenine and compound C were added to the cell cultures in different combinations. Calcium deposition in the cells was examined by Alizarin Red S staining and using the O-cresolphthalein complexone method. To assess the occurrence of autophagy, autophagosomes inside the cells were studied using a transmission electron microscope and green fluorescent microtubule-associated protein 1 light chain 3 (LC3) puncta were examined using a fluorescent microscope. Additionally, protein expression levels of α-smooth muscle actin (α-SMA), runt-related transcription factor 2 (RUNX2), LC3II/I, beclin 1 and 5' adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway-associated proteins were determined by western blot analysis. Metformin increased the number of autophagosomes, green fluorescent LC3 puncta and the levels of LC3II/I, beclin 1, α-SMA and phosphorylated (p)-AMPK in the VSMCs that were treated with β-glycerophosphate when compared to controls; whereas, calcium deposition and the expression levels of RUNX2 and p-mTOR were found to be decreased. Treating the VSMCs with 3-methyladenine or compound C reversed the effects of metformin. The results of the present study suggested that metformin may alleviate β-glycerophosphate-induced calcification of VSMCs, which may be attributed to the activation of AMPK/mTOR signaling pathway-dependent autophagy.
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Affiliation(s)
- Xiaobo Qiu
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, Liaoning 110000, P.R. China.,Department of Orthopaedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Qing Xu
- Department of Orthopaedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Tianhua Xu
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, Liaoning 110000, P.R. China
| | - Pengzhi Wan
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, Liaoning 110000, P.R. China
| | - Zitong Sheng
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, Liaoning 110000, P.R. China
| | - Yiran Han
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, Liaoning 110000, P.R. China
| | - Li Yao
- Department of Nephrology, The First Hospital of China Medical University, Shenyang, Liaoning 110000, P.R. China
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İMAMOĞLU Ş. Oral Glucose-Lowering Agent Treatments in Type 2 Diabetes Mellitus. TURKISH JOURNAL OF INTERNAL MEDICINE 2020. [DOI: 10.46310/tjim.815794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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38
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Jones VC, Dietze EC, Jovanovic-Talisman T, McCune JS, Seewaldt VL. Metformin and Chemoprevention: Potential for Heart-Healthy Targeting of Biologically Aggressive Breast Cancer. Front Public Health 2020; 8:509714. [PMID: 33194937 PMCID: PMC7658387 DOI: 10.3389/fpubh.2020.509714] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 09/24/2020] [Indexed: 12/14/2022] Open
Abstract
Currently, tamoxifen is the only drug approved for reduction of breast cancer risk in premenopausal women. The significant cardiovascular side effects of tamoxifen, coupled with lack of a survival benefit, potential for genotoxicity, and failure to provide a significant risk-reduction for estrogen receptor-negative breast cancer, all contribute to the low acceptance of tamoxifen chemoprevention in premenopausal women at high-risk for breast cancer. While other prevention options exist for postmenopausal women, there is a search for well-tolerated prevention agents that can simultaneously reduce risk of breast cancers, cardiovascular disease, and type-2 diabetes. Metformin is a well-tolerated oral biguanide hypoglycemic agent that is prescribed worldwide to over 120 million individuals with type-2 diabetes. Metformin is inexpensive, safe during pregnancy, and the combination of metformin, healthy lifestyle, and exercise has been shown to be effective in preventing diabetes. There is a growing awareness that prevention drugs and interventions should make the “whole woman healthy.” To this end, current efforts have focused on finding low toxicity alternatives, particularly repurposed drugs for chemoprevention of breast cancer, including metformin. Metformin's mechanisms of actions are complex but clearly involve secondary lowering of circulating insulin. Signaling pathways activated by insulin also drive biologically aggressive breast cancer and predict poor survival in women with breast cancer. The mechanistic rationale for metformin chemoprevention is well-supported by the scientific literature. Metformin is cheap, safe during pregnancy, and has the potential to provide heart-healthy breast cancer prevention. On-going primary and secondary prevention trials will provide evidence whether metformin is effective in preventing breast cancer.
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Affiliation(s)
- Veronica C Jones
- City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Eric C Dietze
- City of Hope Comprehensive Cancer Center, Duarte, CA, United States
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Uusalo P, Järvisalo MJ. Mortality and renal prognosis in isolated metformin-associated lactic acidosis treated with continuous renal replacement therapy and citrate-calcium-anticoagulation. Acta Anaesthesiol Scand 2020; 64:1305-1311. [PMID: 32564362 DOI: 10.1111/aas.13659] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 06/03/2020] [Accepted: 06/05/2020] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Use of metformin increases plasma lactate concentration and may lead to metformin-associated lactic acidosis (MALA). Previous studies have suggested severe MALA to have a mortality of 17%-21%, but have included patients with other coincident conditions such as sepsis. The treatment of choice is continuous renal replacement therapy (CRRT), which has been performed using heparin analogues or no anticoagulation in former studies. MATERIALS AND METHODS Patients admitted to the Intensive Care Unit of Turku University Hospital Finland with lactic acidosis without any other recognizable etiology than concomitant metformin treatment who required CRRT between years 2010 and 2019 were included. CRRT was performed using regional citrate-calcium-anticoagulation. Data extracted included patient demographics, comorbidities, and clinical parameters at 6-hour intervals about 72 hours from admission. Creatinine and estimated glomerular filtration rate (eGFR) were measured at 1 year after MALA. RESULTS A total of 23 patients with isolated MALA were included in the study. Median (IQR) pH was 6.88 (6.81-7.07) and lactate 16.1 (11.9-23.0) mmol/L on admission. Median (IQR) duration of CRRT was 62 (41-70) hours. Seven patients (30%) required mechanical ventilation with a mean duration of 6.0 ± 3.0 days. 90-day mortality was 4.3% and 1-year mortality 13.0%. Creatinine (P = .02) and eGFR (P = .03) remained significantly altered at 1 year of follow-up compared to baseline. CONCLUSIONS MALA can be treated effectively and safely with CRRT and citrate-calcium-anticoagulation, usually required for 2-3 days. Mortality of patients with MALA treated with CRRT is low when other conditions inducing lactic acidosis are excluded. MALA episode may be associated with long-lasting kidney injury.
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Affiliation(s)
- Panu Uusalo
- Department of Anaesthesiology and Intensive Care University of Turku Turku Finland
- Perioperative Services, Intensive Care and Pain Medicine Turku University Hospital Turku Finland
| | - Mikko J. Järvisalo
- Department of Anaesthesiology and Intensive Care University of Turku Turku Finland
- Perioperative Services, Intensive Care and Pain Medicine Turku University Hospital Turku Finland
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Khunti K, Gomes MB, Kosiborod M, Nicolucci A, Pocock S, Rathmann W, Shestakova MV, Shimomura I, Watada H, Chen H, Cid-Ruzafa J, Fenici P, Hammar N, Tang F, Ji L. Metformin discontinuation in patients beginning second-line glucose-lowering therapy: results from the global observational DISCOVER study programme. BMJ Open 2020; 10:e034613. [PMID: 32868349 PMCID: PMC7462233 DOI: 10.1136/bmjopen-2019-034613] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
OBJECTIVES To evaluate the extent to which patients with type 2 diabetes discontinue metformin therapy when initiating second-line treatment and factors associated with metformin discontinuation, using baseline data from the DISCOVER study programme. DESIGN DISCOVER is a 3-year, prospective, observational study programme including data from 38 countries across 6 continents from 2014 to 2019. SETTING Primary and secondary healthcare centres, hospitals and specialist diabetes centres in both urban and rural locations. PARTICIPANTS A total of 15 992 patients with type 2 diabetes initiating second-line glucose-lowering therapy. PRIMARY AND SECONDARY OUTCOME MEASURES The proportion of patients who discontinued metformin as a second-line therapy and the factors associated with this treatment change. RESULTS Of the 14 668 patients (from 37 countries) with valid treatment data, 11 837 (80.7%) received metformin as first-line glucose-lowering therapy; 8488 (71.7%) received metformin monotherapy and 3349 (28.3%) received metformin as part of a combination therapy. Overall, treatment with metformin was discontinued in 15.1% (1782) of patients who received first-line metformin (14.1% (1194) and 17.6% (588) in those who received metformin as monotherapy and as part of a combination, respectively); this proportion varied across regions from 6.9% (54) in Africa to 20.6% (628) in South-East Asia. On metformin discontinuation, 73.6% (1311) of patients received a non-insulin monotherapy at second line. Factors associated with an increased odds of metformin discontinuation were older age (≥75 years) and having a history of chronic kidney disease. The probability of metformin monotherapy discontinuation was lower in patients from Africa than in those from Europe. CONCLUSIONS A substantial number of patients discontinued taking metformin when beginning second-line therapy. Most of these patients subsequently received a non-insulin monotherapy at second line, in contradiction to international guidelines and potentially leaving them at an increased risk of hyperglycaemia and associated adverse outcomes. TRIAL REGISTRATION NUMBERS NCT02322762 and NCT02226822.
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Affiliation(s)
- Kamlesh Khunti
- Diabetes Research Centre, University of Leicester, Leicester, UK
| | - Marilia B Gomes
- Department of Internal Medicine, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil
| | - Mikhail Kosiborod
- Department of Cardiovascular research, Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA
- Department of Internal Medicine, University of Missouri Kansas City, Kansas City, Missouri, USA
- The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Antonio Nicolucci
- Department of Metabolic Medicine, Center for Outcomes Research and clinical Epidemiology (CORE), Pescara, Italy
| | - Stuart Pocock
- Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK
| | - Wolfgang Rathmann
- Institute for Biometrics and Epidemiology, German Diabetes Center, Düsseldorf, Germany
| | - Marina V Shestakova
- Feberal Scientific Centre of Endocrinology, Endocrinology Research Centre, Moscow, Russian Federation
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Osaka University Hospital, Suita, Osaka, Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University, Bunkyo-ku, Tokyo, Japan
| | | | | | | | - Niklas Hammar
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- AstraZeneca, Gothenburg, Sweden
| | - Fengming Tang
- Department of Cardiovascular research, Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
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Metformin as a Potential Agent in the Treatment of Multiple Sclerosis. Int J Mol Sci 2020; 21:ijms21175957. [PMID: 32825027 PMCID: PMC7503488 DOI: 10.3390/ijms21175957] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/16/2020] [Accepted: 08/17/2020] [Indexed: 12/18/2022] Open
Abstract
Metformin, a synthetic derivative of guanidine, is commonly used as an oral antidiabetic agent and is considered a multi-vector application agent in the treatment of other inflammatory diseases. Recent studies have confirmed the beneficial effect of metformin on immune cells, with special emphasis on immunological mechanisms. Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by various clinical courses. Although the pathophysiology of MS remains unknown, it is most likely a combination of disturbances of the immune system and biochemical pathways with a disruption of blood-brain barrier (BBB), and it is strictly related to injury of intracerebral blood vessels. Metformin has properties which are greatly desirable for MS therapy, including antioxidant, anti-inflammatory or antiplatelet functions. The latest reports relating to the cardiovascular disease confirm an increased risk of ischemic events in MS patients, which are directly associated with a coagulation cascade and an elevated pro-thrombotic platelet function. Hence, this review examines the potential favourable effects of metformin in the course of MS, its role in preventing inflammation and endothelial dysfunction, as well as its potential antiplatelet role.
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Shin JI, Sang Y, Chang AR, Dunning SC, Coresh J, Inker LA, Selvin E, Ballew SH, Grams ME. The FDA Metformin Label Change and Racial and Sex Disparities in Metformin Prescription among Patients with CKD. J Am Soc Nephrol 2020; 31:1847-1858. [PMID: 32660971 PMCID: PMC7460896 DOI: 10.1681/asn.2019101119] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 04/14/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND In 2016, the Food and Drug Administration (FDA) changed labeling regarding metformin contraindications in patients with diabetes and CKD from using serum creatinine-based thresholds to using eGFR-based thresholds. Because race and sex affect serum creatinine levels independently of GFR, the earlier creatinine-based contraindication may have inadvertently caused racial and sex disparities in metformin prescription among patients with low eGFR. METHODS In an analysis of 15,946 Black and White primary care patients with diabetes and eGFR≥30 ml/min per 1.73 m2 in a large health system (the primary cohort), we assessed the association of race and sex with metformin prescription across eGFR level before and after the FDA label change. For a replication cohort, we meta-analyzed data from 36 cohorts with 1,051,723 patients from OptumLabs Data Warehouse. RESULTS In the primary cohort, before the label change, Black patients with eGFR of 30-44 ml/min per 1.73 m2 were prescribed metformin less often than White counterparts (adjusted prevalence ratio [aPR], 0.65; 95% confidence interval [95% CI], 0.52 to 0.82); this disparity was significantly attenuated after the label change (aPR, 0.90; 95% CI, 0.74 to 1.09; P value for interaction by period =0.04). Results were consistent in the replication cohorts. Men with eGFR of 30-44 ml/min per 1.73 m2 received metformin prescriptions less often than women counterparts before the label change; this was nonsignificantly attenuated after the label change, but we found significant attenuation in the replication cohorts (aPRpre-label change, 0.76; 95% CI, 0.73 to 0.79; aPRpost-label change, 0.85; 95% CI, 0.83 to 0.88; P value for interaction by period <0.001). CONCLUSIONS The metformin label change to an eGFR-based contraindication may have reduced racial and sex disparities in metformin prescription in moderate kidney dysfunction.
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Affiliation(s)
- 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
- OptumLabs Visiting Fellow, OptumLabs, Cambridge, Massachusetts
| | - Alex R Chang
- Kidney Health Research Institute, Geisinger, Danville, Pennsylvania
| | | | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Lesley A Inker
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | - Elizabeth Selvin
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Shoshana H Ballew
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - 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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Ono K, Wada H, Satoh-Asahara N, Inoue H, Uehara K, Funada J, Ogo A, Horie T, Fujita M, Shimatsu A, Hasegawa K. Effects of Metformin on Left Ventricular Size and Function in Hypertensive Patients with Type 2 Diabetes Mellitus: Results of a Randomized, Controlled, Multicenter, Phase IV Trial. Am J Cardiovasc Drugs 2020; 20:283-293. [PMID: 31721026 PMCID: PMC7266803 DOI: 10.1007/s40256-019-00381-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background Metformin is the most widely used oral antihyperglycemic agent for patients with type 2 diabetes mellitus (T2DM). Despite the possible benefits of metformin on diabetes mellitus (DM) and heart failure (HF), acute or unstable HF remains a precaution for its use. Objective The aim of the present prospective randomized controlled trial was to assess whether metformin treatment has beneficial effects on patients with T2DM with hypertension without overt HF. Methods A total of 164 patients (92 males, 72 females; median age 66 years) were included in this study. Patients with T2DM with a history of hypertension were randomized 1:1 to treatment for 1 year with either metformin (metformin-treated group) or other hypoglycemic agents (control group). The primary endpoints were changes in brain natriuretic peptide (BNP) levels, left ventricular (LV) mass index, and indicators of LV diastolic function. We also evaluated changes in both clinical findings and blood laboratory examination data. Results We observed no significant changes between baseline and 1-year post-treatment in LV mass index, BNP levels, or E/e′ (early diastolic transmitral flow velocity/early diastolic mitral annular velocity; an indicator of LV diastolic function) in either the metformin-treated (n = 83) or the control (n = 81) groups. The metformin-treated group had a significant reduction of body mass index (BMI) and low-density lipoprotein cholesterol (LDL-C), but the control group did not. We determined that renal function, including serum creatinine and estimated glomerular filtration rate, deteriorated significantly in the control group but not in the metformin-treated group. Conclusion LV mass and diastolic function were not affected after 1 year of metformin treatment in patients with T2DM. However, we observed benefits in terms of reductions in both BMI and LDL-C levels and preservation of renal function. Trial Registration UMIN000006504. Registered 7 October 2011.
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Wilcox T, De Block C, Schwartzbard AZ, Newman JD. Diabetic Agents, From Metformin to SGLT2 Inhibitors and GLP1 Receptor Agonists: JACC Focus Seminar. J Am Coll Cardiol 2020; 75:1956-1974. [PMID: 32327107 PMCID: PMC7219531 DOI: 10.1016/j.jacc.2020.02.056] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/25/2020] [Accepted: 02/28/2020] [Indexed: 12/11/2022]
Abstract
Given the intersection between diabetes mellitus and cardiovascular disease (CVD), pharmacologic agents used to treat type 2 diabetes mellitus must show cardiovascular safety. Comorbid conditions, including heart failure and chronic kidney disease, are increasingly prevalent in patients with diabetes; therefore, they also play a large role in drug safety. Although biguanides, sulfonylurea, glitazones, and dipeptidyl peptidase 4 inhibitors have variable effects on cardiovascular events, sodium glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have consistently shown safety and reduction in cardiovascular events in patients with established CVD. These medications are becoming essential tools for cardioprotection for patients with diabetes and CVD. They may also have roles in primary prevention and renal protection. This paper will review the cardiovascular impact, adverse effects, and possible mechanisms of action of pharmacologic agents used to treat patients with type 2 diabetes.
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Affiliation(s)
- Tanya Wilcox
- Department of Medicine, Division of Cardiology, New York University School of Medicine, New York, New York
| | - Christophe De Block
- Department of Endocrinology, Diabetology & Metabolism, University of Antwerp-Antwerp University Hospital, Antwerp, Belgium
| | - Arthur Z Schwartzbard
- Department of Medicine, Division of Cardiology, New York University School of Medicine, New York, New York; Center for the Prevention of CVD, Department of Medicine, Division of Cardiology, New York University School of Medicine, New York, New York
| | - Jonathan D Newman
- Department of Medicine, Division of Cardiology, New York University School of Medicine, New York, New York; Center for the Prevention of CVD, Department of Medicine, Division of Cardiology, New York University School of Medicine, New York, New York.
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Abad K, Kien C, Ganta K. A Unique Case of Metformin-associated Severe Lactic Acidosis Without Preexisting Renal Disease: Perspectives on Prolonged Dialysis and Education for Prevention. Cureus 2020; 12:e7564. [PMID: 32382466 PMCID: PMC7202579 DOI: 10.7759/cureus.7564] [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: 03/16/2020] [Accepted: 04/06/2020] [Indexed: 11/05/2022] Open
Abstract
Metabolic acidosis is a common disorder defined by an imbalance in the body's acid-base balance. Identifying the cause of acidosis is critical for its management. We describe a case of acute renal failure with lactic acidosis in a 69-year-old man who was taking metformin for type 2 diabetes. The patient presented with decreased urine output after two weeks of intermittent nausea and vomiting. During this time, the patient had continued to take limited fluids and medication, including lisinopril and metformin. Physical exam on initial evaluation was remarkable only for hypertension and minimal abdominal tenderness. However, laboratory tests revealed a severe lactic acidosis and renal failure with hyperkalemia. The patient had normal renal function and a normal urine albumin level three weeks prior. Broad-spectrum antibiotics and sodium bicarbonate were administered, followed by hemodialysis. During hemodialysis, the patient became hemodynamically unstable, requiring vasopressors. Post-dialysis, the lactic acidosis worsened, prompting the initiation of additional prolonged dialysis during the first hospital day. After the second lengthy dialysis, the patient's condition improved significantly and he was discharged on hospital day 12, with the diagnosis of metformin-associated lactic acidosis (MALA) in the setting of acute tubular necrosis from gastrointestinal fluid loss accompanied by the continued use of an angiotensin-converting enzyme inhibitor. After discharge, his renal function returned to normal. Severe lactic acidosis from metformin is relatively rare. Metformin has a large volume of distribution and accumulates in erythrocytes and intestinal cells, resulting in less efficient removal with dialysis and rebound lactic acidosis. Prolonged dialysis may be necessary for MALA to improve outcomes. Identifying metformin levels may help in diagnosis and management. However, the means to Identify metformin levels are not widely available. Patients receiving metformin should be counseled to stop metformin and seek medical care in the setting of illnesses. This is particularly important given the frequency of metformin prescription and the common use of renin-angiotensin system blockade in patients with type 2 diabetes, which increases the risk of kidney dysfunction.
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Affiliation(s)
- Kashif Abad
- Nephrology, University of New Mexico, Albuquerque, USA
| | - Cassandra Kien
- Biological Sciences, Arizona State University, Tempe, USA
| | - Kavitha Ganta
- Nephrology, Raymond G. Murphy Veterans Affairs Medical Center, Albuquerque, USA
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Garber AJ, Handelsman Y, Grunberger G, Einhorn D, Abrahamson MJ, Barzilay JI, Blonde L, Bush MA, DeFronzo RA, Garber JR, Garvey WT, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Perreault L, Rosenblit PD, Samson S, Umpierrez GE. CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM - 2020 EXECUTIVE SUMMARY. Endocr Pract 2020; 26:107-139. [PMID: 32022600 DOI: 10.4158/cs-2019-0472] [Citation(s) in RCA: 383] [Impact Index Per Article: 76.6] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Al-Hwiesh AK, Abdul-Rahman IS, Noor AS, Nasr-El-Deen MA, Abdelrahman A, El-Salamoni TS, Al-Muhanna FA, Al-Otaibi K, Al-Audah N. The Phantom of Metformin-Induced Lactic Acidosis in End-Stage Renal Disease Patients: Time to Reconsider with Peritoneal Dialysis Treatment. Perit Dial Int 2020; 37:56-62. [DOI: 10.3747/pdi.2015.00309] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Accepted: 05/17/2016] [Indexed: 01/22/2023] Open
Abstract
ObjectiveMetformin continues to be the safest and most widely used antidiabetic drug. In spite of its well-known benefits; metformin use in end-stage renal disease (ESRD) patients is still restricted. Little has been reported about the effect of peritoneal dialysis (PD) on metformin clearance and the phantom of lactic acidosis deprives ESRD patients from metformin therapeutic advantages. Peritoneal dialysis is probably a safeguard against lactic acidosis, and it is likely that using this drug would be feasible in this group of patients.Material and methodsThe study was conducted on 83 PD patients with type 2 diabetes mellitus. All patients were on automated PD (APD). Metformin was administered in a dose of 500 - 1,000 mg daily. Patients were monitored for glycemic control. Plasma lactic acid and plasma metformin levels were monitored on a scheduled basis. Peritoneal fluid metformin levels were measured. In addition, the relation between plasma metformin and plasma lactate was studied.ResultsMean fasting blood sugar (FBS) was 10.9 ± 0.5 and 7.8 ± 0.7, and mean hemoglobin A1-C (HgA1C) was 8.2 ± 0.8 and 6.4 ± 1.1 at the beginning and end of the study, respectively (p < 0.001). The mean body mass index (BMI) was 29.1 ± 4.1 and 27.3 ± 4.5 at the beginning and at the end of the study, respectively (p < 0.001). The overall mean plasma lactate level across all blood samples was 1.44 ± 0.6. Plasma levels between 2 and 3 mmol/L were found in 11.8% and levels of 3 - 3.6 mmol/L in 2.4% plasma samples. Hyperlactemia (level > 2 and < 5 mmol/L) was not associated with overt acidemia. None of our patients had lactic acidosis (levels > 5 mmol/L). Age ≥ 60 was a predictor for hyperlactemia. No relationship was found between plasma metformin and lactate levels.ConclusionMetformin may be used with caution in a particular group of ESRD patients who are on APD. Metformin allows better diabetic control with significant reduction of BMI. Information on the relationship between metformin and plasma lactate levels is lacking. Peritoneal dialysis appears to be a safeguard against the development of lactic acidosis in this group of patients.
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Affiliation(s)
| | | | - Abdul-Salam Noor
- Department of Internal Medicine, Queens University, Kingston, Ontario, Canada
| | | | - Abdalla Abdelrahman
- Nephrology Division, King Fahd Hospital of the University, University of Dammam, Saudi Arabia; and Department of Electrical Engineering, Queens University, Kingston, Ontario, Canada
| | | | - Fahd A. Al-Muhanna
- Department of Internal Medicine, Queens University, Kingston, Ontario, Canada
| | - Khalid Al-Otaibi
- Department of Internal Medicine, Queens University, Kingston, Ontario, Canada
| | - Nehad Al-Audah
- Department of Internal Medicine, Queens University, Kingston, Ontario, Canada
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Pugliese G, Penno G, Natali A, Barutta F, Di Paolo S, Reboldi G, Gesualdo L, De Nicola L. Diabetic kidney disease: new clinical and therapeutic issues. Joint position statement of the Italian Diabetes Society and the Italian Society of Nephrology on "The natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and impaired renal function". J Nephrol 2020; 33:9-35. [PMID: 31576500 PMCID: PMC7007429 DOI: 10.1007/s40620-019-00650-x] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIMS This joint document of the Italian Diabetes Society and the Italian Society of Nephrology reviews the natural history of diabetic kidney disease (DKD) in the light of the recent epidemiological literature and provides updated recommendations on anti-hyperglycemic treatment with non-insulin agents. DATA SYNTHESIS Recent epidemiological studies have disclosed a wide heterogeneity of DKD. In addition to the classical albuminuric phenotype, two new albuminuria-independent phenotypes have emerged, i.e., "nonalbuminuric renal impairment" and "progressive renal decline", suggesting that DKD progression toward end-stage kidney disease (ESKD) may occur through two distinct pathways, albuminuric and nonalbuminuric. Several biomarkers have been associated with decline of estimated glomerular filtration rate (eGFR) independent of albuminuria and other clinical variables, thus possibly improving ESKD prediction. However, the pathogenesis and anatomical correlates of these phenotypes are still unclear. Also the management of hyperglycemia in patients with type 2 diabetes and impaired renal function has profoundly changed during the last two decades. New anti-hyperglycemic drugs, which do not cause hypoglycemia and weight gain and, in some cases, seem to provide cardiorenal protection, have become available for treatment of these individuals. In addition, the lowest eGFR safety thresholds for some of the old agents, particularly metformin and insulin secretagogues, have been reconsidered. CONCLUSIONS The heterogeneity in the clinical presentation and course of DKD has important implications for the diagnosis, prognosis, and possibly treatment of this complication. The therapeutic options for patients with type 2 diabetes and impaired renal function have substantially increased, thus allowing a better management of these individuals.
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Affiliation(s)
- Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.
- Endocrine and Metabolic Unit, Sant'Andrea University Hospital, Rome, Italy.
| | - Giuseppe Penno
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Diabetes Unit, University Hospital, Pisa, Italy
| | - Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Unit of Internal Medicine, University Hospital, Pisa, Italy
| | - Federica Barutta
- Department of Medical Sciences, University of Turin, Turin, Italy
| | | | | | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, "Aldo Moro" University, Bari, Italy
- Nephrology, Dialysis and Transplantation Unit, "Policlinico" University Hospital, Bari, Italy
| | - Luca De Nicola
- Nephrology and Dialysis Unit, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
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Yendapally R, Sikazwe D, Kim SS, Ramsinghani S, Fraser‐Spears R, Witte AP, La‐Viola B. A review of phenformin, metformin, and imeglimin. Drug Dev Res 2020; 81:390-401. [DOI: 10.1002/ddr.21636] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 12/05/2019] [Accepted: 12/23/2019] [Indexed: 12/14/2022]
Affiliation(s)
| | - Donald Sikazwe
- Feik School of PharmacyUniversity of the Incarnate Word San Antonio Texas
| | - Subin S. Kim
- Feik School of PharmacyUniversity of the Incarnate Word San Antonio Texas
| | - Sushma Ramsinghani
- Feik School of PharmacyUniversity of the Incarnate Word San Antonio Texas
| | | | - Amy P. Witte
- Feik School of PharmacyUniversity of the Incarnate Word San Antonio Texas
| | - Brittany La‐Viola
- School of PharmacyUniversity of Maryland Eastern Shore Princess Anne Maryland
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Vaughan EM, Rueda JJ, Samson SL, Hyman DJ. Reducing the Burden of Diabetes Treatment: A Review of Low-cost Oral Hypoglycemic Medications. Curr Diabetes Rev 2020; 16:851-858. [PMID: 32026779 PMCID: PMC7415714 DOI: 10.2174/1573399816666200206112318] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 12/24/2019] [Accepted: 01/20/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND The vast majority of individuals diagnosed with diabetes are low/middle income and may have access to only three of the 11 oral hypoglycemic medications (OHMs) due to cost: metformin intermediate release (IR) or extended release (ER), sulfonylureas (glimepiride, glipizide, glyburide), and pioglitazone. Sulfonylureas and pioglitazone have had significant controversy related to potential adverse events, but it remains unclear whether these negative outcomes are class, drug, or dose-related. OBJECTIVE We conducted a narrative review of low-cost OHMs. METHODS We evaluated the maximum recommended (MAX) compared to the most effective (EFF) daily dose, time-to-peak change in HbA1c levels, and adverse events of low-cost oral hypoglycemic medications. RESULTS We found that the MAX was often greater than the EFF: metformin IR/ER (MAX: 2,550/2,000 mg, EFF: 1,500-2,000/1,500-2,000 mg), glipizide IR/ER (MAX: 40/20 mg, EFF: 20/5 mg), glyburide (MAX: 20 mg, EFF: 2.5-5.0 mg), pioglitazone (MAX: 45 mg, EFF: 45 mg). Time-to-peak change in HbA1c levels occurred at weeks 12-20 (sulfonylureas), 25-39 (metformin), and 25 (pioglitazone). Glimepiride was not associated with weight gain, hypoglycemia, or negative cardiovascular events relative to other sulfonylureas. Cardiovascular event rates did not increase with lower glyburide doses (p<0.05). Glimepiride and pioglitazone have been successfully used in renal impairment. CONCLUSION Metformin, glimepiride, and pioglitazone are safe and efficacious OHMs. Prescribing at the EFF rather than the MAX may avoid negative dose-related outcomes. OHMs should be evaluated as individual drugs, not generalized as a class, due to different dosing and adverse-event profiles; Glimepiride is the preferred sulfonylurea since it is not associated with the adverse events as others in its class.
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Affiliation(s)
- Elizabeth M Vaughan
- Division of General Internal Medicine, Department of Medicine, Baylor College of Medicine, University in Houston, Texas, TX 77030, United States
| | - Jaime J Rueda
- Division of General Internal Medicine, Department of Medicine, Baylor College of Medicine, University in Houston, Texas, TX 77030, United States
| | - Susan L Samson
- Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Baylor College of Medicine, University in Houston, Texas, TX 77030, United States
| | - David J Hyman
- Division of General Internal Medicine, Department of Medicine, Baylor College of Medicine, University in Houston, Texas, TX 77030, United States
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