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Asaad GF, Doghish AS, Rashad AA, El-Dakroury WA. Exploring cutting-edge approaches in diabetes care: from nanotechnology to personalized therapeutics. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:2443-2458. [PMID: 39453501 PMCID: PMC11919990 DOI: 10.1007/s00210-024-03532-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 10/08/2024] [Indexed: 10/26/2024]
Abstract
Diabetes mellitus (DM) is a persistent condition characterized by high levels of glucose in the blood due to irregularities in the secretion of insulin, its action, or both. The disease was believed to be incurable until insulin was extracted, refined, and produced for sale. In DM, insulin delivery devices and insulin analogs have improved glycemic management even further. Sulfonylureas, biguanides, alpha-glucosidase inhibitors, and thiazolidinediones are examples of newer-generation medications having high efficacy in decreasing hyperglycemia as a result of scientific and technological advancements. Incretin mimetics, dual glucose-dependent insulinotropic polypeptide, GLP-1 agonists, PPARs, dipeptidyl peptidase-4 inhibitors, anti-CD3 mAbs, glucokinase activators, and glimins as targets have all performed well in recent clinical studies. Considerable focus was placed on free FA receptor 1 agonist, protein tyrosine phosphatase-1B inhibitors, and Sparc-related modular calcium-binding protein 1 which are still being studied. Theranostics, stem cell therapy, gene therapy, siRNA, and nanotechnology are some of the new therapeutic techniques. Traditional Chinese medicinal plants will also be discussed. This study seeks to present a comprehensive analysis of the latest research advancements, the emerging trends in medication therapy, and the utilization of delivery systems in treating DM. The objective is to provide valuable insights into the application of different pharmaceuticals in the field of diabetes mellitus treatment. Also, the therapeutic approach for diabetic patients infected with COVID-19 will be highlighted. Recent clinical and experimental studies evidence the Egyptian experience. Finally, as per the knowledge of the state of the art, our conclusion and future perspective will be declared.
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Affiliation(s)
- Gihan F Asaad
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, 11651, Egypt
| | - Ahmed A Rashad
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
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Li D, Zhang Z, Li W, Zhao C, Li X, Pan Z, Li Y. Exploring Inflammatory Changes in the Peripheral Blood of Type 2 Diabetes Mellitus in China. J Inflamm Res 2025; 18:1679-1688. [PMID: 39925936 PMCID: PMC11806746 DOI: 10.2147/jir.s501105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 01/27/2025] [Indexed: 02/11/2025] Open
Abstract
Objective Type 2 diabetes mellitus (T2DM) is a serious, chronic metabolic disease globally and its pathogenesis is not completely understood yet. This study aimed to thoroughly investigate the fluctuation of inflammatory markers in the peripheral blood of patients with T2DM, which are rarely reported. Methods Peripheral blood samples from patients with T2DM and healthy individuals, as well as their clinical information, were collected at the Second Affiliated Hospital of Soochow University. Flow cytometry was used to analyse the immune cells and cytokines in the peripheral blood. CCK-8 assay was performed to detect the viability of THP-1 cell after treatment with 5 mΜ or 50 mΜ glucose. Flow cytometry, Western Blotting and qPCR were used to analyse the apoptosis of monocytes or THP-1 cells. Results The numbers of white blood cells, lymphocytes, and neutrophils substantially increased with elevated IL-6 levels. There was a significant decrease in monocytes due to increased cell apoptosis caused by sustained high glucose stimulation. Hyperglycemia reduced monocyte viability and altered monocyte subgroups by increasing the number of intermediate and non-classical monocytes. Conclusion In summary, our work reveals that patients with T2DM do have variations of peripheral inflammation biomarkers, especially monocytes.
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Affiliation(s)
- Dan Li
- Department of Clinical Laboratory, Children’s Hospital of Soochow University, Suzhou, Jiangsu, 215025, People’s Republic of China
- Department of Clinical Laboratory, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, People’s Republic of China
| | - Zhiru Zhang
- Department of Human Resources, the Affiliated Hospital of Nantong University, Nantong, Jiangsu, 22600, People’s Republic of China
| | - Wen Li
- Department of Clinical Laboratory, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, People’s Republic of China
| | - Chenhao Zhao
- Department of Clinical Laboratory, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, People’s Republic of China
| | - Xiaochen Li
- Department of Clinical Laboratory, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, People’s Republic of China
| | - Zhen Pan
- Department of Clinical Laboratory, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, People’s Republic of China
| | - Yang Li
- Department of Clinical Laboratory, Children’s Hospital of Soochow University, Suzhou, Jiangsu, 215025, People’s Republic of China
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Islam L, Jose D, Alkhalifah M, Blaibel D, Chandrabalan V, Pappachan JM. Comparative efficacy of sodium glucose cotransporter-2 inhibitors in the management of type 2 diabetes mellitus: A real-world experience. World J Diabetes 2024; 15:463-474. [PMID: 38591092 PMCID: PMC10999032 DOI: 10.4239/wjd.v15.i3.463] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 01/02/2024] [Accepted: 02/18/2024] [Indexed: 03/15/2024] Open
Abstract
BACKGROUND Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are a class of drugs with modest antidiabetic efficacy, weight loss effect, and cardiovascular benefits as proven by multiple randomised controlled trials (RCTs). However, real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse. AIM To study the comparative efficacy and safety of SGLT-2i using real-world clinical data. METHODS We evaluated the comparative efficacy data of 3 SGLT-2i drugs (dapagliflozin, canagliflozin, and empagliflozin) used for treating patients with type 2 diabetes mellitus. Data on the reduction of glycated hemoglobin (HbA1c), body weight, blood pressure (BP), urine albumin creatinine ratio (ACR), and adverse effects were recorded retrospectively. RESULTS Data from 467 patients with a median age of 64 (14.8) years, 294 (62.96%) males and 375 (80.5%) Caucasians were analysed. Median diabetes duration was 16.0 (9.0) years, and the duration of SGLT-2i use was 3.6 (2.1) years. SGLT-2i molecules used were dapagliflozin 10 mg (n = 227; 48.6%), canagliflozin 300 mg (n = 160; 34.3%), and empagliflozin 25 mg (n = 80; 17.1). Baseline median (interquartile range) HbA1c in mmol/mol were: dapagliflozin - 78.0 (25.3), canagliflozin - 80.0 (25.5), and empagliflozin - 75.0 (23.5) respectively. The respective median HbA1c reduction at 12 months and the latest review (just prior to the study) were: 66.5 (22.8) & 69.0 (24.0), 67.0 (16.3) & 66.0 (28.0), and 67.0 (22.5) & 66.5 (25.8) respectively (P < 0.001 for all comparisons from baseline). Significant improvements in body weight (in kilograms) from baseline to study end were noticed with dapagliflozin - 101 (29.5) to 92.2 (25.6), and canagliflozin 100 (28.3) to 95.3 (27.5) only. Significant reductions in median systolic and diastolic BP, from 144 (21) mmHg to 139 (23) mmHg; (P = 0.015), and from 82 (16) mmHg to 78 (19) mmHg; (P < 0.001) respectively were also observed. A significant reduction of microalbuminuria was observed with canagliflozin only [ACR 14.6 (42.6) at baseline to 8.9 (23.7) at the study end; P = 0.043]. Adverse effects of SGLT-2i were as follows: genital thrush and urinary infection - 20 (8.8%) & 17 (7.5%) with dapagliflozin; 9 (5.6%) & 5 (3.13%) with canagliflozin; and 4 (5%) & 4 (5%) with empagliflozin. Diabetic ketoacidosis was observed in 4 (1.8%) with dapagliflozin and 1 (0.63%) with canagliflozin. CONCLUSION Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c, body weight, and better than those reported in RCTs, with low side effect profiles. A review of large-scale real-world data is needed to inform better clinical practice decision making.
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Affiliation(s)
- Lubna Islam
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
| | - Dhanya Jose
- Department of Community Medicine, Goa Medical College, Goa 403202, India
| | - Mohammed Alkhalifah
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Department of Family Medicine, King Faisal Specialist Hospital, Riyadh 11564, Saudi Arabia
| | - Dania Blaibel
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
| | - Vishnu Chandrabalan
- Department of Data Science, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, All Saints Building, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom
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Wang N, Zhang C. Recent Advances in the Management of Diabetic Kidney Disease: Slowing Progression. Int J Mol Sci 2024; 25:3086. [PMID: 38542060 PMCID: PMC10970506 DOI: 10.3390/ijms25063086] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/28/2024] [Accepted: 03/05/2024] [Indexed: 01/03/2025] Open
Abstract
Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD), and it heightens the risk of cardiovascular incidents. The pathogenesis of DKD is thought to involve hemodynamic, inflammatory, and metabolic factors that converge on the fibrotic pathway. Genetic predisposition and unhealthy lifestyle practices both play a significant role in the development and progression of DKD. In spite of the recent emergence of angiotensin receptors blockers (ARBs)/angiotensin converting enzyme inhibitor (ACEI), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid receptors antagonists (NS-MRAs), current therapies still fail to effectively arrest the progression of DKD. Glucagon-like peptide 1 receptor agonists (GLP-1RAs), a promising class of agents, possess the potential to act as renal protectors, effectively slowing the progression of DKD. Other agents, including pentoxifylline (PTF), selonsertib, and baricitinib hold great promise as potential therapies for DKD due to their anti-inflammatory and antifibrotic properties. Multidisciplinary treatment, encompassing lifestyle modifications and drug therapy, can effectively decelerate the progression of DKD. Based on the treatment of heart failure, it is recommended to use multiple drugs in combination rather than a single-use drug for the treatment of DKD. Unearthing the mechanisms underlying DKD is urgent to optimize the management of DKD. Inflammatory and fibrotic factors (including IL-1, MCP-1, MMP-9, CTGF, TNF-a and TGF-β1), along with lncRNAs, not only serve as diagnostic biomarkers, but also hold promise as therapeutic targets. In this review, we delve into the potential mechanisms and the current therapies of DKD. We also explore the additional value of combing these therapies to develop novel treatment strategies. Drawing from the current understanding of DKD pathogenesis, we propose HIF inhibitors, AGE inhibitors, and epigenetic modifications as promising therapeutic targets for the future.
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Affiliation(s)
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
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Winter J. Embedding guidelines into clinical practice. PRACTICAL DIABETES 2023. [DOI: 10.1002/pdi.2447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
Affiliation(s)
- Judy Winter
- Advanced Nurse Practitioner & Diabetes Specialist Nurse, Park Medical Practice Greater Preston Clinical Commissioning Group Preston UK
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Watanabe K, Sato E, Mishima E, Miyazaki M, Tanaka T. What's New in the Molecular Mechanisms of Diabetic Kidney Disease: Recent Advances. Int J Mol Sci 2022; 24:570. [PMID: 36614011 PMCID: PMC9820354 DOI: 10.3390/ijms24010570] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/23/2022] [Accepted: 12/26/2022] [Indexed: 12/30/2022] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease, including end-stage kidney disease, and increases the risk of cardiovascular mortality. Although the treatment options for DKD, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists, have advanced, their efficacy is still limited. Thus, a deeper understanding of the molecular mechanisms of DKD onset and progression is necessary for the development of new and innovative treatments for DKD. The complex pathogenesis of DKD includes various different pathways, and the mechanisms of DKD can be broadly classified into inflammatory, fibrotic, metabolic, and hemodynamic factors. Here, we summarize the recent findings in basic research, focusing on each factor and recent advances in the treatment of DKD. Collective evidence from basic and clinical research studies is helpful for understanding the definitive mechanisms of DKD and their regulatory systems. Further comprehensive exploration is warranted to advance our knowledge of the pathogenesis of DKD and establish novel treatments and preventive strategies.
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Affiliation(s)
- Kimio Watanabe
- Dialysis Center, Tohoku University Hospital, Sendai 980-8574, Japan
| | - Emiko Sato
- Division of Clinical Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
| | - Eikan Mishima
- Division of Nephrology, Rheumatology and Endocrinology, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan
- Institute of Metabolism and Cell Death, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Mariko Miyazaki
- Dialysis Center, Tohoku University Hospital, Sendai 980-8574, Japan
- Division of Nephrology, Rheumatology and Endocrinology, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan
| | - Tetsuhiro Tanaka
- Division of Nephrology, Rheumatology and Endocrinology, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan
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Furuya F, Fujita Y, Matsuo N, Minamino H, Oguri Y, Isomura N, Ikeda K, Takesue K, Li Y, Kondo A, Mano F, Inagaki N. Liver autophagy-induced valine and leucine in plasma reflect the metabolic effect of sodium glucose co-transporter 2 inhibitor dapagliflozin. EBioMedicine 2022; 86:104342. [PMID: 36423374 PMCID: PMC9682354 DOI: 10.1016/j.ebiom.2022.104342] [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: 10/11/2021] [Revised: 09/14/2022] [Accepted: 10/19/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Sodium glucose co-transporter 2 (SGLT2) inhibitors are anti-diabetic drugs for type 2 diabetes that lower blood glucose levels and body weight. It is of special interest that SGLT2 inhibitors also improve liver metabolism and fatty liver. Liver is an important organ in regulation of energy metabolism, but the metabolic action of SGLT inhibitors in liver remains unclear. METHODS We investigated the factors associated with the beneficial effects of dapagliflozin, a SGLT2 inhibitor, in the liver after confirming its glucose-lowering and weight loss effects using an obesity and diabetes mouse model. We also performed clinical study of patients with type 2 diabetes to explore candidate biomarkers that reflect the beneficial action of dapagliflozin in the liver. FINDINGS In animal study, dapagliflozin induced autophagy in the liver (LC3-II to LC3-I expression ratio: P < 0·05 vs. control), and valine and leucine levels were increased in plasma (P < 0·01 vs. control) as well as in liver (P < 0·05 vs. control). Thus, increased plasma valine and leucine levels are potential biomarkers for improved liver metabolism. Clinical study found that valine and leucine levels were markedly higher in patients treated with dapagliflozin (valine: P < 0·05 vs. control, leucine: P < 0·01 vs. control) than those not treated after one week intervention. INTERPRETATION Dapagliflozin improves liver metabolism via hepatic autophagy, and plasma valine and leucine levels may reflect its metabolic effect. FUNDING AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan Society for the Promotion of Science (JSPS), Japan Agency for Medical Research and Development (AMED), Novo Nordisk Pharma Ltd., and Japan Foundation for Applied Enzymology, and MSD Life Science Foundation International.
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Affiliation(s)
| | - Yoshihito Fujita
- Corresponding author. Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Shogoin, Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
| | | | | | | | | | | | | | | | | | | | - Nobuya Inagaki
- Corresponding author. Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Shogoin, Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
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Ohkoshi-Yamada M, Kamimura K, Kimura A, Tanaka Y, Nagayama I, Yakubo S, Abe H, Yokoo T, Sakamaki A, Kamimura H, Terai S. Effects of a selective PPARα modulator, sodium-glucose cotransporter 2 inhibitor, and statin on the myocardial morphology of medaka nonalcoholic fatty liver disease model. Biochem Biophys Res Commun 2022; 625:116-121. [PMID: 35952608 DOI: 10.1016/j.bbrc.2022.07.117] [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: 07/24/2022] [Revised: 07/27/2022] [Accepted: 07/31/2022] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic dysregulation and is linked with various cardiovascular complications, which often lead to poor prognostic outcomes. To develop a standard therapy for NAFLD and to urgently address its complications, the current study aimed to investigate the mechanisms of NAFLD-related heart disease and the therapeutic effects of drugs targeting various metabolic pathways. METHODS To explore the mechanism of NAFLD-related heart disease, a medaka model of high-fat diet-induced NAFLD was utilized. The gross structural, histological, and inflammatory changes in the myocardium were evaluated in a time-dependent manner. In addition, the therapeutic effects of medicines used for NAFLD treatment including, selective peroxisome proliferator-activated receptor α modulator (SPPARMα, pemafibrate), sodium-glucose cotransporter 2 (SGLT2) inhibitor (tofogliflozin), and statin (pitavastatin), and their combinations on heart pathology were evaluated. To determine the mechanisms underlying the therapeutic effects, the expression of genes related to liver inflammation was assessed via whole transcriptome sequencing analysis. RESULTS The fish with NAFLD-related heart injury presented with cardiomyocyte hypertrophy, which led to cardiac hypertrophy. This morphological change was caused by the infiltration of inflammatory cells, including macrophages and CD4- and CD8-positive lymphocytes, in the cardiac wall and the expression of transforming growth factor beta 1 in the cardiomyocytes. Further, the livers of the fish had upregulated expressions of senescence-associated secretory phenotype-related genes. Treatment with pemafibrate, tofogliflozin, and pitavastatin reduced these changes and, consequently, cardiomyopathy. CONCLUSION Our results demonstrated that NAFLD-related heart disease was attributed to the senescence-associated secretory phenotype-induced inflammatory activity in the cardiac wall, which resulted in myocardial hypertrophy. Moreover, the effects of SPPARMα, SGLT2 inhibitor, and statin on NAFLD-related heart disease were evident in the medaka NAFLD model.
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Affiliation(s)
- Marina Ohkoshi-Yamada
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-Dori, Chuo-Ku, Niigata, Japan
| | - Kenya Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-Dori, Chuo-Ku, Niigata, Japan; Department of General Medicine, Niigata University School of Medicine, 1-757, Asahimachi-Dori, Chuo-Ku, Niigata, Japan.
| | - Atsushi Kimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-Dori, Chuo-Ku, Niigata, Japan
| | - Yuto Tanaka
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-Dori, Chuo-Ku, Niigata, Japan
| | - Itsuo Nagayama
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-Dori, Chuo-Ku, Niigata, Japan
| | - Shunta Yakubo
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-Dori, Chuo-Ku, Niigata, Japan
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-Dori, Chuo-Ku, Niigata, Japan
| | - Takeshi Yokoo
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-Dori, Chuo-Ku, Niigata, Japan
| | - Akira Sakamaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-Dori, Chuo-Ku, Niigata, Japan
| | - Hiroteru Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-Dori, Chuo-Ku, Niigata, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-Dori, Chuo-Ku, Niigata, Japan
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Wang Y, Shen QL, Xin Q, Sun B, Zhang S, Fang QH, Shi YX, Niu WY, Lin JN, Li CJ. MCAD activation by empagliflozin promotes fatty acid oxidation and reduces lipid deposition in NASH. J Mol Endocrinol 2022; 69:415-430. [PMID: 35900373 DOI: 10.1530/jme-22-0022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 07/28/2022] [Indexed: 11/08/2022]
Abstract
Medium-chain acyl-CoA dehydrogenase (MCAD) is one of the significant enzymes involved in the β-oxidation of mitochondrial fatty acids. MCAD deficiency affects the β-oxidation of fatty acid and leads to lipid deposition in multiple organs, but little is known about its importance in nonalcoholic steatohepatitis (NASH). Empagliflozin is revealed to effectively improve NASH by increasing research, whereas the specific mechanism still has to be explored. Human liver tissues of patients with or without NASH were obtained for proteomic analysis to screen proteins of interest. db/db mice were given empagliflozin by gavage for 8 weeks. The expression of MCAD and signaling molecules involved in hepatic lipid metabolism was evaluated in human liver, mice and HL7702 cells. We found that the MCAD levels in the liver were significantly reduced in NASH patients compared to patients without NASH. Protein-protein interaction network analysis showed that MCAD was highly correlated with forkhead box A2 (FOXA2) and protein kinase AMP-activated catalytic subunit alpha (PRKAA). AMPK/FOXA2/MCAD signaling pathway was detected to be inhibited in the liver of NASH patients. Decreased expression of MCAD was also observed in the livers of db/db mice and hepatocyte treated with palmitic acid and glucose. Of note, empagliflozin could upregulate MCAD expression by activating AMPK/FOXA2 signaling pathway, reduce lipid deposition and improve NASH in vivo and in vitro. This research demonstrated that MCAD is a key player of hepatic lipid deposition and its targeting partially corrects NASH. MCAD thus may be a potential therapeutic target for the treatment of NASH.
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Affiliation(s)
- Yi Wang
- Department of Endocrinology, Health Management Center, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin, China
| | - Qi-Ling Shen
- Department of Endocrinology, Health Management Center, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin, China
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Qi Xin
- Department of Pathology, The Third Central Clinical College of Tianjin Medical University, Tianjin Third Central Hospital, Tianjin Key Laboratory of Artificial Cells, Tianjin, China
| | - Bei Sun
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Shi Zhang
- Department of Endocrinology, Health Management Center, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin, China
| | - Qian-Hua Fang
- Department of Endocrinology, Health Management Center, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin, China
| | - Ying-Xin Shi
- Department of Endocrinology, Health Management Center, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin, China
| | - Wen-Yan Niu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Jing-Na Lin
- Department of Endocrinology, Health Management Center, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin, China
| | - Chun-Jun Li
- Department of Endocrinology, Health Management Center, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin, China
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Vanholder R, Conway PT, Gallego D, Scheres E, Wieringa F. The European Kidney Health Alliance (EKHA) and the Decade of the KidneyTM. Nephrol Dial Transplant 2022; 38:1113-1122. [PMID: 35790139 DOI: 10.1093/ndt/gfac211] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Indexed: 11/13/2022] Open
Abstract
The European Kidney Health Alliance (EKHA) is an advocacy organization that defends the case of the kidney patients and the nephrological community at the level of the European Union (EU), and from there, top to bottom, also at the national level of the EU member states and the EU-associated countries. The Decade of the KidneyTM is a global initiative launched by the American Association of Kidney Patients (AAKP) to create greater awareness and organize patient demands for long overdue innovation in kidney care. This article describes the medical and patient burden of kidney disease, the history of EKHA, its major activities and tools for policy action and the need for innovation. We then describe the Decade of the KidneyTM initiative, the rationale why EKHA joined this activity to emanate parallel action at the European side, the novel professionalized structure of EKHA, and its immediate targets. The final aim is to align all major stakeholders for an action plan on kidney disease comparable to Europe's successful Beating Cancer Plan, with the additional intent that the EKHA model is applied also by the respective national kidney-related societies to create a broad mobilization at all levels. The ultimate aims are that the EU considers chronic kidney disease (CKD) as a major health and health-economic problem, to consequently have CKD included as a key health research target by the European Commission, and to improve quality of life and outcomes for all kidney patients.
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Affiliation(s)
- Raymond Vanholder
- European Kidney Health Alliance (EKHA), Brussels, Belgium.,Nephrology Section, Department of Internal Medicine and Pediatrics, University Hospital Ghent, Ghent, Belgium
| | - Paul T Conway
- Policy and Global Affairs, American Association of Kidney Patients (AAKP), Washington, DC, US
| | - Daniel Gallego
- European Kidney Patient's Federation (EKPF), Vienna, Austria
| | - Eveline Scheres
- European Kidney Health Alliance (EKHA), Brussels, Belgium.,Buiten de Lijnen, Utrecht, The Netherlands
| | - Fokko Wieringa
- Department of Nephrology and Hypertension, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.,Department of Autonomous Therapeutics, Imec, Eindhoven, The Netherlands
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11
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Cen J, Han Y, Liu Y, Hu H. Evaluated Glomerular Filtration Rate Is Associated With Non-alcoholic Fatty Liver Disease: A 5-Year Longitudinal Cohort Study in Chinese Non-obese People. Front Nutr 2022; 9:916704. [PMID: 35782950 PMCID: PMC9244698 DOI: 10.3389/fnut.2022.916704] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 05/30/2022] [Indexed: 12/12/2022] Open
Abstract
ObjectiveEvidence regarding the association between evaluated glomerular filtration rate (eGFR) and non-alcoholic fatty liver disease (NAFLD) is still limited. On that account, the purpose of our research is to survey the link of evaluated eGFR on NAFLD.MethodsThis study is a retrospective cohort study. Which consecutively and non-selectively collected a total of 16,138 non-obese participants in a Chinese hospital from January 2010 to December 2014. We then used the Cox proportional-hazards regression model to explore the relationship between baseline eGFR and NAFLD risk. A Cox proportional hazards regression with cubic spline functions and smooth curve fitting (the cubic spline smoothing) was used to identify the non-linear relationship between eGFR and NAFLD. Additionally, we also performed a series of sensitivity analyses and subgroup analyses. Data had been uploaded to the DATADRYAD website.ResultsThe mean age of the included individuals was 43.21 ± 14.95 years old, and 8,467 (52.47%) were male. The mean baseline eGFR was 98.83 ± 22.80 mL/min per 1.73m2. During a median follow-up time of 35.8 months, 2,317 (14.36%) people experienced NAFLD. After adjusting covariates, the results showed that eGFR was negatively associated with incident NAFLD (HR = 0.983, 95%CI: 0.980, 0.985). There was also a non-linear relationship between eGFR and NAFLD, and the inflection point of eGFR was 103.489 mL/min per 1.73 m2. The effect sizes (HR) on the left and right sides of the inflection point were 0.988 (0.984, 0.991) and 0.971 (0.963, 0.979), respectively. And the sensitive analysis demonstrated the robustness of our results. Subgroup analysis showed that eGFR was more strongly associated with incident NAFLD in diastolic blood pressure (DBP) < 90 mmHg, fasting plasma glucose (FPG) ≤ 6.1 mmol/L, high-density lipoprotein cholesterol (HDL-c) < 1 mmol/L, and alanine aminotransferase (ALT) ≥ 40 U/L participants. In contrast, the weaker association was probed in those with DBP ≥ 90 mmHg, ALT < 40 U/L, FPG > 6.1 mmol/L, and HDL-c ≥ 1 mmol/L.ConclusionThis study demonstrates a negative and non-linear association between eGFR and incident NAFLD in the Chinese non-obese population. eGFR is strongly related to NAFLD when eGFR is above 103 mL/min per 1.73 m2. From a therapeutic perspective, it makes sense to maintain eGFR levels within the inflection point to 130 mL/min/1.73 m2.
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Affiliation(s)
- Ji Cen
- Department of Nephrology, Hechi People’s Hospital, Hechi, China
| | - Yong Han
- Department of Emergency, Shenzhen Second People’s Hospital, Shenzhen, China
- Department of Emergency, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
- Shenzhen University Health Science Center, Shenzhen, China
| | - Yufei Liu
- Shenzhen University Health Science Center, Shenzhen, China
- Department of Neurosurgery, Shenzhen Second People’s Hospital, Shenzhen, China
- Department of Neurosurgery, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Haofei Hu
- Shenzhen University Health Science Center, Shenzhen, China
- Department of Nephrology, Shenzhen Second People’s Hospital, Shenzhen, China
- Department of Nephrology, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
- *Correspondence: Haofei Hu,
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12
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Tuttle KR, Agarwal R, Alpers CE, Bakris GL, Brosius FC, Kolkhof P, Uribarri J. Molecular Mechanisms and Therapeutic Targets for Diabetic Kidney Disease. Kidney Int 2022; 102:248-260. [PMID: 35661785 DOI: 10.1016/j.kint.2022.05.012] [Citation(s) in RCA: 259] [Impact Index Per Article: 86.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 04/29/2022] [Accepted: 05/10/2022] [Indexed: 12/12/2022]
Abstract
Diabetic kidney disease has a high global disease burden and substantially increases risk of kidney failure and cardiovascular events. Despite treatment, there is substantial residual risk of disease progression with existing therapies. Therefore, there is an urgent need to better understand the molecular mechanisms driving diabetic kidney disease to help identify new therapies that slow progression and reduce associated risks. Diabetic kidney disease is initiated by diabetes-related disturbances in glucose metabolism, which then trigger other metabolic, hemodynamic, inflammatory, and fibrotic processes that contribute to disease progression. This review summarizes existing evidence on the molecular drivers of diabetic kidney disease onset and progression, focusing on inflammatory and fibrotic mediators-factors that are largely unaddressed as primary treatment targets and for which there is increasing evidence supporting key roles in the pathophysiology of diabetic kidney disease. Results from recent clinical trials highlight promising new drug therapies, as well as a role for dietary strategies, in treating diabetic kidney disease.
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Affiliation(s)
- Katherine R Tuttle
- Providence Medical Research Center, Providence Health Care, Spokane, Washington, USA; Institute of Translational Health Sciences, Kidney Research Institute, and Nephrology Division, University of Washington, Seattle, Washington, USA.
| | - Rajiv Agarwal
- Nephrology Division, Indiana University School of Medicine, Indianapolis, Indiana, USA; Nephrology Division, VA Medical Center, Indianapolis, Indiana, USA
| | - Charles E Alpers
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - George L Bakris
- American Heart Association Comprehensive Hypertension Center at the University of Chicago Medicine, Chicago, Illinois, USA
| | - Frank C Brosius
- Department of Medicine, College of Medicine, University of Arizona, Tucson, Arizona, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA; Department of Physiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Peter Kolkhof
- Cardiovascular Precision Medicines, Pharmaceuticals, Research & Development, Bayer AG, Wuppertal, Germany
| | - Jaime Uribarri
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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13
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Luo Q, Leley SP, Bello E, Dhami H, Mathew D, Bhatwadekar AD. Dapagliflozin protects neural and vascular dysfunction of the retina in diabetes. BMJ Open Diabetes Res Care 2022; 10:e002801. [PMID: 35577387 PMCID: PMC9114950 DOI: 10.1136/bmjdrc-2022-002801] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 04/22/2022] [Indexed: 11/04/2022] Open
Abstract
INTRODUCTION Dapagliflozin, a sodium-glucose transporter inhibitor, effectively reduces blood glucose and is indicated for individuals with kidney diseases and cardiovascular disorders. In this study, we further expand the therapeutic benefit of dapagliflozin in the neural and vascular retina, with the potential to effectively manage diabetic retinopathy (DR), the most common complication of diabetes. RESEARCH DESIGN AND METHODS Db/db mice, an animal model of type 2 diabetes, were treated with dapagliflozin orally, and the electroretinogram (ERG) response and acellular capillary numbers were assessed. Messenger RNA levels of inflammatory cytokines were studied using real-time quantitative (q)PCR. We assessed endothelial cell migration in a scratch wound assay and retinal glucose uptake using human retinal endothelial cells. RESULTS The dapagliflozin treatment improved the ERG b-wave amplitude and decreased acellular capillary numbers. The scratch wound assay demonstrated a reduction in wound closure after dapagliflozin treatment. Retinal glucose uptake reduced after dapagliflozin treatment compared with the respective controls. CONCLUSIONS Our studies suggest that dapagliflozin treatment effectively corrects neural and vascular dysfunction of the retina in diabetes. This effect is mediated by a decrease in inflammation and improved glycemic control. In addition, dapagliflozin exhibits decreased wound healing and glucose uptake, which could benefit the retina. Thus, dapagliflozin could be helpful in the management of DR, with multimodal therapeutic effects.
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Affiliation(s)
- Qianyi Luo
- Department of Ophthalmology, Indiana University, Indianapolis, Indiana, USA
| | - Sameer P Leley
- School of Medicine, Indiana University, Indianapolis, Indiana, USA
| | - Erika Bello
- Department of Ophthalmology, Indiana University, Indianapolis, Indiana, USA
| | - Hurshdeep Dhami
- Department of Ophthalmology, Indiana University, Indianapolis, Indiana, USA
| | - Deepa Mathew
- Department of Ophthalmology, Indiana University, Indianapolis, Indiana, USA
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Pandey AK, Dhingra NK, Hibino M, Gupta V, Verma S. Sodium-glucose cotransporter 2 inhibitors in heart failure with reduced or preserved ejection fraction: a meta-analysis. ESC Heart Fail 2022; 9:942-946. [PMID: 35112512 PMCID: PMC8934917 DOI: 10.1002/ehf2.13805] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 12/19/2021] [Accepted: 12/28/2021] [Indexed: 01/10/2023] Open
Abstract
AIMS Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to be an effective therapy in improving heart failure outcomes. We conducted a meta-analysis of randomized controlled trials to evaluate the efficacy of SGLT2 inhibitors in heart failure patients with either a reduced or preserved ejection fraction. METHODS AND RESULTS We searched MEDLINE and EMBASE for large (≥1000 patients) randomized controlled trials evaluating the effects of SGLT2 inhibitors compared with placebo in the setting of heart failure until September 2021. Our primary outcome was the composite of heart failure hospitalization and cardiovascular death, and secondary outcomes included all-cause mortality and total heart failure hospitalizations. We pooled hazard ratios and risk ratios and evaluated risk of bias with the Cochrane Collaboration tool. Four randomized controlled trials (DAPA HF, EMPEROR-Preserved, EMPEROR-Reduced, and SOLOIST-WHF) were included (n = 15 684); two of which evaluated patients with a reduced LVEF, one of which evaluated patients with a preserved LVEF, and one of which included both. Treatment with SGLT2 inhibitors resulted in a significant reduction in the composite of CV death and heart failure hospitalization (HR: 0.76, 95% CI: 0.70, 0.82, I2 : 0%, P < 0.00001). This was consistent in sub-groups of patients with LVEF ≤40% (n = 9199, HR: 0.74, 95% CI: 0.68, 0.81, I2 : 0%) and LVEF >40% (n = 6482, HR: 0.78, 95% CI: 0.68, 0.89, I2 : 0%, P-for-interaction: 0.57), as well as in sub-groups of patients with and without diabetes mellitus at baseline (P-for-interaction: 0.81). SGLT2 inhibitors were associated with a significant reduction in cardiovascular death (HR: 0.87, 95% CI: 0.79, 0.97, I2 : 0%, P < 0.00001) and total heart failure hospitalization (RR: 0.71, 95% CI: 0.67, 0.76, I2 : 0%, P < 0.00001); although a potential trend towards reduced all-cause mortality was noted with SGLT2 inhibitors, no statistically significant difference was observed (HR: 0.91, 95% CI: 0.83, 1.00, I2 : 14%, P = 0.05). CONCLUSIONS Sodium-glucose cotransporter 2 inhibitors reduce cardiovascular death and heart failure hospitalization among patients with heart failure, regardless of LVEF status.
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Affiliation(s)
- Arjun K. Pandey
- Michael G. DeGroote School of MedicineMcMaster UniversityHamiltonOntarioCanada
| | - Nitish K. Dhingra
- Division of Cardiac Surgery, St. Michael's HospitalUniversity of TorontoTorontoOntarioCanada
| | - Makoto Hibino
- Division of Cardiac Surgery, St. Michael's HospitalUniversity of TorontoTorontoOntarioCanada
- Department of SurgeryUniversity of TorontoTorontoOntarioCanada
| | - Vijay Gupta
- Division of Cardiac Surgery, St. Michael's HospitalUniversity of TorontoTorontoOntarioCanada
| | - Subodh Verma
- Division of Cardiac Surgery, St. Michael's HospitalUniversity of TorontoTorontoOntarioCanada
- Department of SurgeryUniversity of TorontoTorontoOntarioCanada
- Institute of Medical SciencesUniversity of TorontoTorontoOntarioCanada
- Keenan Research Center in the Li Ka Shing Knowledge Institute of St. Michael's HospitalUniversity of TorontoTorontoOntarioCanada
- Department of Pharmacology and ToxicologyUniversity of TorontoTorontoOntarioCanada
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15
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Yip ASY, Leong S, Teo YH, Teo YN, Syn NLX, See RM, Wee CF, Chong EY, Lee CH, Chan MY, Yeo TC, Wong RCC, Chai P, Sia CH. Effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors on serum urate levels in patients with and without diabetes: a systematic review and meta-regression of 43 randomized controlled trials. Ther Adv Chronic Dis 2022; 13:20406223221083509. [PMID: 35342538 PMCID: PMC8949773 DOI: 10.1177/20406223221083509] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 02/08/2022] [Indexed: 01/10/2023] Open
Abstract
Objectives Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been found to reduce serum urate in patients with type 2 diabetes mellitus. To evaluate if this effect applies to both patients with and without diabetes, we conducted a systematic review and meta-analysis of SGLT2 inhibitors on serum urate levels in this population. Methods Four electronic databases (PubMed, Embase, Cochrane and SCOPUS) were searched on 25 September 2021 for articles published from 1 January 2000 up to 25 September 2021, for studies that examined the effect of SGLT2 inhibitors on serum urate in study subjects. Random-effects meta-analysis was performed, with subgroup analyses on the type of SGLT2 inhibitor agent administered, presence of type 2 diabetes mellitus, presence of chronic kidney disease and drug dose. Results A total of 43 randomized controlled trials, with a combined cohort of 31,921 patients, were included. Both patients with [-31.48 μmol/L; 95% confidence interval (CI): -37.35 to -25.60] and without diabetes (-91.38 μmol/L; 95% CI: -126.53 to -56.24) on SGLT2 inhibitors had significantly lower urate levels when compared with placebo. This treatment effect was similarly observed across different types of SGLT2 inhibitors. However, in type 2 diabetes mellitus (T2DM) patients with chronic kidney disease, the reduction in serum urate with SGLT2 inhibitors became insignificant (95% CI: -22.17 to 5.94, p < 0.01). Conclusion This study demonstrated that SGLT2 inhibitors are beneficial in reducing serum urate in patients with and without diabetes. SGLT2 inhibitors could therefore contribute to the general treatment of hyperuricaemia.
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Affiliation(s)
- Alicia Swee Yan Yip
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Shariel Leong
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore 117597
| | - Yao Hao Teo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yao Neng Teo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Nicholas L X Syn
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ray Meng See
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Caitlin Fern Wee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Elliot Yeung Chong
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Chi-Hang Lee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Mark Y Chan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Tiong-Cheng Yeo
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Raymond C C Wong
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ping Chai
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ching-Hui Sia
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Kowalska K, Walczak J, Femlak J, Młynarska E, Franczyk B, Rysz J. Empagliflozin-A New Chance for Patients with Chronic Heart Failure. Pharmaceuticals (Basel) 2021; 15:47. [PMID: 35056104 PMCID: PMC8779904 DOI: 10.3390/ph15010047] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/20/2021] [Accepted: 12/27/2021] [Indexed: 11/27/2022] Open
Abstract
The heart failure (HF) epidemic is one of the challenges that has been faced by the healthcare system worldwide for almost 25 years. With an ageing world population and a fast-paced lifestyle that promotes the development of cardiovascular disease, the number of people suffering from heart failure will continue to rise. To improve the treatment regimen and consequently the prognosis and quality of life of heart failure patients, new therapeutic solutions have been introduced, such as an inclusion of Sodium-glucose co-transporter 2 (SGLT-2) inhibitors in a new treatment regimen as announced by the European Society of Cardiology in August 2021. This article focuses on the SGLT2 inhibitor empagliflozin and its use in patients with heart failure. Empagliflozin is a drug originally intended for the treatment of diabetes due to its glycosuric properties, yet its beneficial effects extend beyond lowering glycemia. The pleiotropic effects of the drug include nephroprotection, improving endothelial function, lowering blood pressure and reducing body weight. In this review we discuss the cardioprotective mechanism of the drug in the context of the benefits of empagliflozin use in patients with chronic cardiac insufficiency. Numerous findings confirm that despite its potential limitations, the use of empagliflozin in HF treatment is advantageous and effective.
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Affiliation(s)
| | | | | | - Ewelina Młynarska
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland; (K.K.); (J.W.); (J.F.); (B.F.); (J.R.)
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Zeng S, Delic D, Chu C, Xiong Y, Luo T, Chen X, Gaballa MMS, Xue Y, Chen X, Cao Y, Hasan AA, Stadermann K, Frankenreiter S, Yin L, Krämer BK, Klein T, Hocher B. Antifibrotic effects of low dose SGLT2 Inhibition with empagliflozin in comparison to Ang II receptor blockade with telmisartan in 5/6 nephrectomised rats on high salt diet. Biomed Pharmacother 2021; 146:112606. [PMID: 34968924 DOI: 10.1016/j.biopha.2021.112606] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/26/2021] [Accepted: 12/26/2021] [Indexed: 12/13/2022] Open
Abstract
To date, the lowest protective SGLT2 inhibitor dose is unknown. We initially performed a dose-response pilot study in normal rats. Based on the results of this pilot study we compared the cardio-renal effects of the SGLT-2 inhibitor empagliflozin, with placebo or telmisartan in rats with 5/6 nephrectomy (5/6 Nx) on a high salt diet (HSD). The experimental set up was as follows: Sham operation (Sham) with normal diet and placebo; 5/6 Nx with 2% HSD and placebo; 5/6 Nx with HSD and empagliflozin (0.6 mg/kg/day, bid); 5/6 Nx with HSD and telmisartan (5 mg/kg/day, qd). Empagliflozin treatment increased urinary glucose excretion, in parallel to empagliflozin plasma levels, in a dose-dependent manner starting at doses of 1 mg/kg in the pilot study. 5/6Nx rats on HSD treated with this low empagliflozin dose showed significantly reduced cardiac (-34.85%; P < 0.05) and renal (-33.68%; P < 0.05) fibrosis in comparison to 5/6Nx rats on HSD treated with placebo. These effects were comparable to the effects observed when implementing the standard dose (5 mg/kg/day) of telmisartan (cardiac fibrosis: -36.37%; P < 0.01; renal fibrosis; -43.96%; P < 0.01). RNA-sequencing followed by confirmatory qRT-PCR revealed that both telmisartan and empagliflozin exert their cardiac effects on genes involved in vascular cell stability and cardiac iron homeostasis, whereas in the kidneys expression of genes involved in endothelial function and oxidative stress were differentially expressed. Urinary adenosine excretion, a surrogate marker of the tubuloglomerular feedback (TGF) mechanism, was not affected. In conclusion, the antifibrotic properties of low dose empagliflozin were comparable to a standard dose of telmisartan. The underlying pathways appear to be TGF independent.
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Affiliation(s)
- Shufei Zeng
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Department of Nephrology, The First Affiliated Hospital of Jinan University, China; Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Denis Delic
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Chang Chu
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Department of Nephrology, The First Affiliated Hospital of Jinan University, China; Department of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| | - Yingquan Xiong
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Department of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| | - Ting Luo
- Department of Nephrology, The First Affiliated Hospital of Jinan University, China; Department of Nephrology, The Third Affiliated Hospital of Sun Yat-sen University, China
| | - Xiaoyi Chen
- Department of Nephrology, The First Affiliated Hospital of Jinan University, China; Department of Nephrology, Jiangmen Central Hospital, China
| | - Mohamed M S Gaballa
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Faculty of Veterinary Medicine, Benha University, Moshtohor,Toukh, Egypt
| | - Yao Xue
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany
| | - Xin Chen
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Department of Nephrology, The First Affiliated Hospital of Jinan University, China; Department of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| | - Yaochen Cao
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Department of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| | - Ahmed A Hasan
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Institute of Nutritional Sciences, University of Potsdam, Potsdam, Germany; Institute of Pharmacy, Free University of Berlin, Germany
| | - Kai Stadermann
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | | | - Lianghong Yin
- Department of Nephrology, The First Affiliated Hospital of Jinan University, China
| | - Bernhard K Krämer
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; European Center for Angioscience ECAS, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany
| | - Thomas Klein
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Berthold Hocher
- Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China; Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China; Institute of Medical Diagnostics, IMD, Berlin, Berlin, Germany.
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Droebner K, Pavkovic M, Grundmann M, Hartmann E, Goea L, Nordlohne J, Klar J, Eitner F, Kolkhof P. Direct Blood Pressure-Independent Anti-Fibrotic Effects by the Selective Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone in Progressive Models of Kidney Fibrosis. Am J Nephrol 2021; 52:588-601. [PMID: 34515038 DOI: 10.1159/000518254] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 06/30/2021] [Indexed: 12/24/2022]
Abstract
INTRODUCTION The nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated clinical benefits in chronic kidney disease patients with type 2 diabetes. Precise molecular mechanisms responsible for these benefits are incompletely understood. Here, we investigated potential direct anti-fibrotic effects and mechanisms of nonsteroidal MR antagonism by finerenone or SGLT2 inhibition by empagliflozin in 2 relevant mouse kidney fibrosis models: unilateral ureter obstruction and sub-chronic ischemia reperfusion injury. METHODS Kidney fibrosis was induced in mice via unilateral ureteral obstruction or ischemia. In a series of experiments, mice were treated orally with the MR antagonist finerenone (3 or 10 mg/kg), the SGLT2 inhibitor empagliflozin (10 or 30 mg/kg), or in a direct comparison of both drugs. Interstitial myofibroblast accumulation was quantified via alpha-smooth muscle actin and interstitial collagen deposition via Sirius Red/Fast Green staining in both models. Secondary analyses included the assessment of inflammatory cells, kidney mRNA expression of fibrotic markers as well as functional parameters (serum creatinine and albuminuria) in the ischemic model. Blood pressure was measured via telemetry in healthy conscious compound-treated animals. RESULTS Finerenone dose-dependently decreased pathological myofibroblast accumulation and collagen deposition with no effects on systemic blood pressure and inflammatory markers in the tested dose range. Reduced kidney fibrosis was paralleled by reduced kidney plasminogen activator inhibitor-1 (PAI-1) and naked cuticle 2 (NKD2) expression in finerenone-treated mice. In contrast, treatment with empagliflozin strongly increased urinary glucose excretion in both models and reduced ischemia-induced albuminuria but had no effects on kidney myofibroblasts or collagen deposition. DISCUSSION/CONCLUSION Finerenone has direct anti-fibrotic properties resulting in reduced myofibroblast and collagen deposition accompanied by a reduction in renal PAI-1 and NKD2 expression in mouse models of progressive kidney fibrosis at blood pressure-independent dosages.
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Affiliation(s)
- Karoline Droebner
- Cardiovascular Research, Research & Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Mira Pavkovic
- Biomarker Research, Research & Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Manuel Grundmann
- Cardiovascular Research, Research & Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Elke Hartmann
- Research Pathology, Research & Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Laura Goea
- Cardiovascular Research, Research & Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Johannes Nordlohne
- Cardiovascular Research, Research & Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Jürgen Klar
- Cardiovascular Research, Research & Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Frank Eitner
- Cardiovascular Research, Research & Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Peter Kolkhof
- Cardiovascular Research, Research & Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany
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Abstract
Reduction of glucose is the hallmark of diabetes therapy proven to reduce micro- and macro-vascular risk in patients with type 1 diabetes. However glucose-lowering efficacy trials in type 2 diabetes didn't show major cardiovascular benefit. Then, a paradigm change in the treatment of patients with type 2 diabetes has emerged due to the introduction of new blood glucose-lowering agents. Cardiovascular endpoint studies have proven HbA1c-independent cardioprotective effects for GLP-1 receptor agonists and SGLT-2 inhibitors. Furthermore, SGLT-2 inhibitors reduce the risk for heart failure and chronic kidney disease. Mechanisms for these blood glucose independent drug target-related effects are still an enigma. Recent research has shown that GLP-1 receptor agonists might have anti-inflammatory and plaque stabilising effects whereas SGLT-2 inhibitors primarily reduce pre- and after-load of the heart and increase work load efficiency of the heart. In addition, reduction of intraglomerular pressure, improved energy supply chains and water regulation appear to be major mechanisms for renoprotection by SGLT-2 inhibitors. These studies and observations have led to recent changes in clinical recommendations and treatment guidelines for type 2 diabetes. In patients with high or very high cardio-renal risk, SGLT-2 inhibitors or GLP-1 receptor agonists have a preferred recommendation independent of baseline HbA1c levels due to cardioprotection. In patients with chronic heart failure, chronic kidney disease or at respective risks SGLT-2 inhibitors are the preferred choice. Therefore, the treatment paradigm of glucose control in diabetes has changed towards using diabetes drugs with evidence-based organ protection improving clinical prognosis.
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Kolkhof P, Joseph A, Kintscher U. Nonsteroidal mineralocorticoid receptor antagonism for cardiovascular and renal disorders - New perspectives for combination therapy. Pharmacol Res 2021; 172:105859. [PMID: 34461222 DOI: 10.1016/j.phrs.2021.105859] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/16/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023]
Abstract
During the recent 30 years, there has been a dramatic increase in knowledge about the role of aldosterone and the mineralocorticoid receptor (MR) in the pathophysiology of cardiovascular (CV) and kidney diseases. The scientific perspective on the aldosterone/MR ensemble extended from a previously renal epithelial-centered focus on sodium-potassium exchange to a broader view as systemic modulators of extracellular matrix, inflammation and fibrosis. Spironolactone was launched as the first antagonist of aldosterone 27 years before the MR was cloned. It was classified as a potassium-sparing diuretic, based on its initial clinical characterization as a diuretic and its preferred activity to compensate for the potassium loss induced by loop diuretics when used in combination. The second steroidal MR antagonist was eplerenone which was discovered at a time when the role of aldosterone and MR in cardiac fibrosis was rediscovered. The constraint of developing potentially life-threatening hyperkalaemia when used in combination with other inhibitors of the renin-angiotensin-system (RAS) in patients with reduced kidney function initiated extensive research and development activities with the goal to identify novel nonsteroidal MR antagonists with an improved benefit-risk ratio. Here we summarize major current clinical trials with MRAs in different CV and renal diseases. Addition of the nonsteroidal MRA finerenone to optimal RAS blockade recently reduced CV and kidney outcomes in two large phase III trials in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). We provide an outlook on further opportunities for combination therapy of nonsteroidal MRA finerenone with RAS inhibitors and sodium-glucose cotransporter-2 inhibitors (SGLT2i).
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Affiliation(s)
- Peter Kolkhof
- Cardiovascular Research, Research and Early Development, R&D Pharmaceuticals, Bayer AG, Wuppertal, Germany.
| | - Amer Joseph
- Cardiology and Nephrology, Clinical Development, R&D Pharmaceuticals, Bayer AG, Berlin, Germany
| | - Ulrich Kintscher
- Charite - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Cardiovascular-Metabolic-Renal Research Center, 10115 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
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21
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(Type 2 diabetes and heart failure - how to optimize cooperation of cardiologist and diabetologist). COR ET VASA 2021. [DOI: 10.33678/cor.2021.084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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22
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Kolkhof P, Hartmann E, Freyberger A, Pavkovic M, Mathar I, Sandner P, Droebner K, Joseph A, Hüser J, Eitner F. Effects of Finerenone Combined with Empagliflozin in a Model of Hypertension-Induced End-Organ Damage. Am J Nephrol 2021; 52:642-652. [PMID: 34111864 PMCID: PMC8619789 DOI: 10.1159/000516213] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 03/27/2021] [Indexed: 12/19/2022]
Abstract
INTRODUCTION The nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated clinical benefits in CKD patients with type 2 diabetes. Clinical data analyzing the potential value of a combination therapy are currently limited. We therefore investigated cardiorenal protection of respective mono- and combination therapy in a preclinical model of hypertension-induced end-organ damage. METHODS Cardiovascular (CV) morbidity and mortality were studied in hypertensive, N(ω)-nitro-L-arginine methyl ester-treated, renin-transgenic (mRen2)27 rats. Rats (10- to 11-week-old females, n = 13-17/group) were treated once daily orally for up to 7 weeks with placebo, finerenone (1 and 3 mg/kg), empagliflozin (3 and 10 mg/kg), or a combination of the respective low doses. Key outcome parameters included mortality, proteinuria, plasma creatinine and uric acid, blood pressure, and cardiac and renal histology. RESULTS Placebo-treated rats demonstrated a 50% survival rate over the course of 7 weeks. Drug treatment resulted in variable degrees of survival benefit, most prominently in the low-dose combination group with a survival benefit of 93%. Monotherapies of finerenone or empagliflozin dose-dependently reduced proteinuria, while low-dose combination revealed an early, sustained, and over-additive reduction in proteinuria. Empagliflozin induced a strong and dose-dependent increase in urinary glucose excretion which was not influenced by finerenone coadministration in the combination arm. Low-dose combination but not respective low-dose monotherapies significantly reduced plasma creatinine and plasma uric acid after 6 weeks. Treatment with finerenone and the low-dose combination significantly decreased systolic blood pressure after 5 weeks. There was a dose-dependent protection from cardiac and kidney fibrosis and vasculopathy with both agents, while low-dose combination therapy was more efficient than the respective monotherapy dosages on most cardiorenal histology parameters. DISCUSSION/CONCLUSIONS Nonsteroidal MR antagonism by finerenone and SGLT2 inhibition by empagliflozin confer CV protection in preclinical hypertension-induced cardiorenal disease. Combination of these 2 independent modes of action at low dosages revealed efficacious reduction in important functional parameters such as proteinuria and blood pressure, plasma markers including creatinine and uric acid, cardiac and renal lesions as determined by histopathology, and mortality indicating a strong potential for combined clinical use in cardiorenal patient populations.
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Affiliation(s)
- Peter Kolkhof
- Cardiovascular Research, Research and Early Development, R&D Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Elke Hartmann
- Research Pathology, Research and Early Development, R&D Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Alexius Freyberger
- Clinical Pathology, Research and Early Development, R&D Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Mira Pavkovic
- Biomarker Research, Research and Early Development, R&D Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Ilka Mathar
- Cardiovascular Research, Research and Early Development, R&D Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Peter Sandner
- Cardiovascular Research, Research and Early Development, R&D Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Karoline Droebner
- Cardiovascular Research, Research and Early Development, R&D Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Amer Joseph
- Clinical Development, R&D Pharmaceuticals, Bayer AG, Berlin, Germany
| | - Jörg Hüser
- Cardiovascular Research, Research and Early Development, R&D Pharmaceuticals, Bayer AG, Wuppertal, Germany
| | - Frank Eitner
- Cardiovascular Research, Research and Early Development, R&D Pharmaceuticals, Bayer AG, Wuppertal, Germany
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23
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Vanholder R, Annemans L, Bello AK, Bikbov B, Gallego D, Gansevoort RT, Lameire N, Luyckx VA, Noruisiene E, Oostrom T, Wanner C, Wieringa F. Fighting the unbearable lightness of neglecting kidney health: the decade of the kidney. Clin Kidney J 2021; 14:1719-1730. [PMID: 34221379 PMCID: PMC8243275 DOI: 10.1093/ckj/sfab070] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 03/16/2021] [Indexed: 01/08/2023] Open
Abstract
A brief comprehensive overview is provided of the elements constituting the burden of kidney disease [chronic kidney disease (CKD) and acute kidney injury]. This publication can be used for advocacy, emphasizing the importance and urgency of reducing this heavy and rapidly growing burden. Kidney diseases contribute to significant physical limitations, loss of quality of life, emotional and cognitive disorders, social isolation and premature death. CKD affects close to 100 million Europeans, with 300 million being at risk, and is projected to become the fifth cause of worldwide death by 2040. Kidney disease also imposes financial burdens, given the costs of accessing healthcare and inability to work. The extrapolated annual cost of all CKD is at least as high as that for cancer or diabetes. In addition, dialysis treatment of kidney diseases imposes environmental burdens by necessitating high energy and water consumption and producing plastic waste. Acute kidney injury is associated with further increases in global morbidity, mortality and economic burden. Yet investment in research for treatment of kidney disease lags behind that of other diseases. This publication is a call for European investment in research for kidney health. The innovations generated should mirror the successful European Union actions against cancer over the last 30 years. It is also a plea to nephrology professionals, patients and their families, caregivers and kidney health advocacy organizations to draw, during the Decade of the Kidney (2020–30), the attention of authorities to realize changes in understanding, research and treatment of kidney disease.
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Affiliation(s)
- Raymond Vanholder
- Department of Internal Medicine and Pediatrics, Nephrology Section, Ghent University Hospital, Ghent, Belgium.,European Kidney Health Alliance, Brussels, Belgium
| | - Lieven Annemans
- Department of Public Health and Primary Care, Ghent University, Ghent, Belgium.,Department of Public Health, Interuniversity Center for Health Economics Research (I-CHER), Free University of Brussels, Brussels, Belgium
| | - Aminu K Bello
- Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, Canada
| | - Boris Bikbov
- Istituto di Richerche Farmcologiche Mario Negri RICCS, Milan, Italy
| | - Daniel Gallego
- European Kidney Patient Federation (EKPF), Dublin, Ireland.,Spanish Kidney Patient Federation (ALCER), Madrid, Spain
| | - Ron T Gansevoort
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Norbert Lameire
- Department of Internal Medicine and Pediatrics, Nephrology Section, Ghent University Hospital, Ghent, Belgium
| | - Valerie A Luyckx
- Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa.,Renal Division, Brigham and Women's Hospital, Boston, MA, USA
| | - Edita Noruisiene
- European Dialysis and Transplant Nurses Association-European Renal Care Association (EDTNA/ERCA), Nidwalden, Switzerland
| | - Tom Oostrom
- Dutch Kidney Foundation, Bussum, the Netherlands
| | - Christoph Wanner
- Department of Internal Medicine I, Nephrology Section, Würzburg University, Würzburg University Hospital, Würzburg, Germany
| | - Fokko Wieringa
- IMEC Eindhoven, Eindhoven, the Netherlands.,Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, the Netherlands
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24
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Rau M, Thiele K, Hartmann NUK, Schuh A, Altiok E, Möllmann J, Keszei AP, Böhm M, Marx N, Lehrke M. Empagliflozin does not change cardiac index nor systemic vascular resistance but rapidly improves left ventricular filling pressure in patients with type 2 diabetes: a randomized controlled study. Cardiovasc Diabetol 2021; 20:6. [PMID: 33413355 PMCID: PMC7791833 DOI: 10.1186/s12933-020-01175-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 11/15/2020] [Indexed: 12/26/2022] Open
Abstract
Background In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial) treatment with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin significantly reduced heart failure hospitalization (HHF) in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The early separation of the HHF event curves within the first 3 months of the trial suggest that immediate hemodynamic effects may play a role. However, hitherto no data exist on early effects of SGLT2 inhibitors on hemodynamic parameters and cardiac function. Thus, this study examined early and delayed effects of empagliflozin treatment on hemodynamic parameters including systemic vascular resistance index, cardiac index, and stroke volume index, as well as echocardiographic measures of cardiac function. Methods In this placebo-controlled, randomized, double blind, exploratory study patients with T2D were randomized to empagliflozin 10 mg or placebo for a period of 3 months. Hemodynamic and echocardiographic parameters were assessed after 1 day, 3 days and 3 months of treatment. Results Baseline characteristics were not different in the empagliflozin (n = 22) and placebo (n = 20) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3 ± 22.7 g/24 h; day 1: 48.4 ± 34.7 g/24 h; p < 0.001) as well as urinary volume (1740 ± 601 mL/24 h to 2112 ± 837 mL/24 h; p = 0.011) already after one day compared to placebo. Treatment with empagliflozin had no effect on the primary endpoint of systemic vascular resistance index, nor on cardiac index, stroke volume index or pulse rate at any time point. In addition, echocardiography showed no difference in left ventricular systolic function as assessed by left ventricular ejections fraction and strain analysis. However, empagliflozin significantly improved left ventricular filling pressure as assessed by a reduction of early mitral inflow velocity relative to early diastolic left ventricular relaxation (E/eʹ) which became significant at day 1 of treatment (baseline: 9.2 ± 2.6; day 1: 8.5 ± 2.2; p = 0.005) and remained apparent throughout the study. This was primarily attributable to reduced early mitral inflow velocity E (baseline: 0.8 ± 0.2 m/s; day 1: 0.73 ± 0.2 m/sec; p = 0.003). Conclusions Empagliflozin treatment of patients with T2D has no significant effect on hemodynamic parameters after 1 or 3 days, nor after 3 months, but leads to rapid and sustained significant improvement of diastolic function. Trial registration EudraCT Number: 2016-000172-19; date of registration: 2017-02-20 (clinicaltrialregister.eu)
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Affiliation(s)
- Matthias Rau
- Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Kirsten Thiele
- Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Niels-Ulrik Korbinian Hartmann
- Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Alexander Schuh
- Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Ertunc Altiok
- Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Julia Möllmann
- Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany
| | - András P Keszei
- Center for Translational & Clinical Research Aachen (CTC-A), RWTH Aachen University, Aachen, Germany
| | - Michael Böhm
- Department of Internal Medicine III, University Hospital Saarland, Saarland University, Homburg/Saar, Germany
| | - Nikolaus Marx
- Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany.
| | - Michael Lehrke
- Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Pauwelsstraße 30, 52074, Aachen, Germany
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25
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Cheon SY, Song J. The Association between Hepatic Encephalopathy and Diabetic Encephalopathy: The Brain-Liver Axis. Int J Mol Sci 2021; 22:ijms22010463. [PMID: 33466498 PMCID: PMC7796499 DOI: 10.3390/ijms22010463] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/02/2021] [Accepted: 01/03/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatic encephalopathy (HE) is one of the main consequences of liver disease and is observed in severe liver failure and cirrhosis. Recent studies have provided significant evidence that HE shows several neurological symptoms including depressive mood, cognitive dysfunction, impaired circadian rhythm, and attention deficits as well as motor disturbance. Liver disease is also a risk factor for the development of diabetes mellitus. Diabetic encephalopathy (DE) is characterized by cognitive dysfunction and motor impairment. Recent research investigated the relationship between metabolic changes and the pathogenesis of neurological disease, indicating the importance between metabolic organs and the brain. Given that a diverse number of metabolites and changes in the brain contribute to neurologic dysfunction, HE and DE are emerging types of neurologic disease. Here, we review significant evidence of the association between HE and DE, and summarise the common risk factors. This review may provide promising therapeutic information and help to design a future metabolic organ-related study in relation to HE and DE.
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Affiliation(s)
- So Yeong Cheon
- Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju 27478, Korea;
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Jeollanam-do, Korea
- Correspondence: ; Tel.: +82-61-379-2706; Fax: +82-61-375-5834
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26
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Gillard P, Schnell O, Groop PH. The nephrological perspective on SGLT-2 inhibitors in type 1 diabetes. Diabetes Res Clin Pract 2020; 170:108462. [PMID: 32971152 DOI: 10.1016/j.diabres.2020.108462] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/10/2020] [Accepted: 09/16/2020] [Indexed: 12/19/2022]
Abstract
Prevalence of type 1 diabetes mellitus (T1DM) is globally continuously increasing. T1DM is accompanied by a high risk of developing cardiovascular and renal comorbidities and is one of the leading causes of end-stage renal disease (ESRD). However, current therapeutic approaches for chronic and/or diabetic kidney disease (CKD/DKD) existed for a long time, and offer room for improvement, particularly in T1DM. In 2019, the European Medicines Agency (EMA) approved a first sodium/glucose co-transporter 2 inhibitor (SGLT-2i) and a first dual SGLT-1/-2i to improve glycaemic control, as an adjunctive treatment to insulin in persons with T1DM and a body mass index ≥27 kg/m2. Of note, SGLT-1/2is and SGLT-2is are not approved by the Food and Drug Administration (FDA) as an adjunct treatment in T1DM, nor approved for the treatment of CKD or DKD by EMA and FDA. SGLT is have shown to mediate different renoprotective effects in type 2 diabetes mellitus in corresponding cardiovascular and renal outcome trials. First efficacy trials offer insights into potential positive effects on renal function and kidney disease of SGLTis in T1DM. This review summarizes and discusses latest available data on SGLT inhibition and provides an update on the nephrological perspective on SGLTis, specifically in T1DM.
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Affiliation(s)
- Pieter Gillard
- Department of Endocrinology, University Hospitals Leuven, KU Leuven, Belgium
| | - Oliver Schnell
- Sciarc GmbH, Baierbrunn, Germany; Forschergruppe Diabetes e.V., München - Neuherberg, Germany.
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland; Abdominal Centre, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland; Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
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27
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Cieslik LK, Cresswell NR, Fineberg D, Mariani JA, Patel HC. Prescription trends and costs of diabetes medications in Australia between 2003 and 2019: an analysis and review of the literature. Intern Med J 2020; 52:841-847. [PMID: 33197121 DOI: 10.1111/imj.15137] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 11/11/2020] [Accepted: 11/12/2020] [Indexed: 01/10/2023]
Abstract
BACKGROUND Since the turn of the century, the prevalence of diabetes mellitus in Australia has increased, primarily due to rising rates of Type 2 diabetes. Simultaneously, the landscape of diabetes medications has evolved significantly. The change in prescribing trends and public spending on diabetes medications within Australia during this period are not well defined. AIMS To establish the frequency and cost of dispensed diabetes medications in the Australian public healthcare system between 2003 and 2019. METHODS We performed a longitudinal nationwide observational study using data obtained from the Pharmaceutical Benefits Scheme (PBS) and Medicare Benefits Schedule websites, which contain information on frequency and spending of diabetes medications dispensed in Australia. RESULTS The total number of PBS-subsidised prescriptions dispensed for diabetes increased from 5 218 690 in 2003 to 12 188 568 in 2019, and spending increased from $117 241 031 to $598 904 983. Of the non-insulin agents, metformin was consistently the most frequently dispensed agent, with a rapid growth in metformin combination tablets. Dispensation of sulphonylureas and thiazolidinediones have declined, with a simultaneous increase in dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists. CONCLUSIONS Our data show a large growth in the use of diabetes medications between 2003 and 2019. The rapid growth in dispensing of drugs with proven cardiovascular and renal benefits reflect the evolving approach of diabetes treatment, from a historical approach targeting glycaemic control alone, to a modern individualised approach targeting specific co-morbidities.
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Affiliation(s)
- Luke K Cieslik
- Alfred Hospital, Melbourne, Victoria, Australia.,Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Nikki R Cresswell
- Alfred Hospital, Melbourne, Victoria, Australia.,Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia
| | - Daniel Fineberg
- Alfred Hospital, Melbourne, Victoria, Australia.,Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Justin A Mariani
- Alfred Hospital, Melbourne, Victoria, Australia.,Central Clinical School, Monash University, Melbourne, Victoria, Australia.,Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Hitesh C Patel
- Alfred Hospital, Melbourne, Victoria, Australia.,Central Clinical School, Monash University, Melbourne, Victoria, Australia.,Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
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Radlinger B, Hornsteiner F, Folie S, Salvenmoser W, Haubner BJ, Schuetz T, Haas S, Ress C, Adolph TE, Salzmann K, Weiss B, Tilg H, Kaser S. Cardioprotective effects of short-term empagliflozin treatment in db/db mice. Sci Rep 2020; 10:19686. [PMID: 33184414 PMCID: PMC7665199 DOI: 10.1038/s41598-020-76698-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 08/28/2020] [Indexed: 12/21/2022] Open
Abstract
Sodium glucose transporter (SGLT)-2 inhibitors have consistently shown cardioprotective effects independent of the glycemic status of treated patients. In this study we aimed to investigate underlying mechanisms of short-term empagliflozin treatment in a mouse model of type II diabetes. Male db/db mice were fed a western type diet with or without enrichment with empagliflozin for 7 days. While glucose tolerance was significantly improved in empagliflozin treated mice, body weight and fasting insulin levels were comparable in both groups. Cardiac insulin signaling activity indicated by reduced proteinkinase B (AKT) phosphorylation was significantly decreased in the empagliflozin treated group. Remarkably, mitochondrial mass estimated by citrate synthase activity was significantly elevated in empagliflozin treated mice. Accordingly, mitochondrial morphology was significantly altered upon treatment with empagliflozin as analysed by transmission electron microscopy. Additionally, short-term empagliflozin therapy was associated with a changed cardiac tissue cytokine expression in favor of an anti-inflammatory pattern. Our data suggest that early cardioprotection in empagliflozin treated mice is independent of a reduction in body weight or hyperinsulinemia. Ameliorated mitochondrial ultrastructure, attenuated cardiac insulin signaling and diminished cardiac inflammation might contribute to the cardioprotective effects of empagliflozin.
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Affiliation(s)
- Bernhard Radlinger
- Department of Internal Medicine I, Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Florian Hornsteiner
- Department of Internal Medicine I, Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Sabrina Folie
- Department of Internal Medicine I, Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Willi Salvenmoser
- Insitute of Zoology and Center of Molecular Biosciences Innsbruck (CBMI), Leopold Franzens University Innsbruck, Innsbruck, Austria
| | - Bernhard J Haubner
- Department of Internal Medicine III, Medical University Innsbruck, Innsbruck, Austria
| | - Thomas Schuetz
- Department of Internal Medicine III, Medical University Innsbruck, Innsbruck, Austria
| | - Simone Haas
- Department of Internal Medicine I, Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Claudia Ress
- Department of Internal Medicine I, Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Timon E Adolph
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Karin Salzmann
- Department of Internal Medicine I, Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Bernhard Weiss
- Department of Internal Medicine I, Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria
| | - Susanne Kaser
- Department of Internal Medicine I, Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.
- Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
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Scheen AJ. Sodium-glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2020; 16:556-577. [PMID: 32855502 DOI: 10.1038/s41574-020-0392-2] [Citation(s) in RCA: 168] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/03/2020] [Indexed: 02/07/2023]
Abstract
The management of type 2 diabetes mellitus (T2DM) is becoming increasingly complex. Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are the newest antidiabetic agents for T2DM. By targeting the kidney, they have a unique mechanism of action, which results in enhanced glucosuria, osmotic diuresis and natriuresis, thereby improving glucose control with a limited risk of hypoglycaemia and exerting additional positive effects such as weight loss and the lowering of blood pressure. Several outcome studies with canagliflozin, dapagliflozin or empagliflozin reported a statistically significant reduction in major cardiovascular events, hospitalization for heart failure and progression to advanced renal disease in patients with T2DM who have established atherosclerotic cardiovascular disease, several cardiovascular risk factors, albuminuric mild to moderate chronic kidney disease or heart failure. Current guidelines proposed a new paradigm in the management of T2DM, with a preferential place for SGLT2is, after metformin, in patients with atherosclerotic cardiovascular disease, heart failure and progressive kidney disease. Ongoing trials might extend the therapeutic potential of SGLT2is in patients with, but also without, T2DM. This Review provides an update of the current knowledge on SGLT2is, moving from their use as glucose-lowering medications to their new positioning as cardiovascular and renal protective agents.
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Affiliation(s)
- André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium.
- Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.
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Zhao R, Lu Z, Yang J, Zhang L, Li Y, Zhang X. Drug Delivery System in the Treatment of Diabetes Mellitus. Front Bioeng Biotechnol 2020; 8:880. [PMID: 32850735 PMCID: PMC7403527 DOI: 10.3389/fbioe.2020.00880] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Diabetes mellitus has been described as a chronic endocrine and metabolic disease, which is characterized by hyperglycemia and the coexistence of multiple complications. At present, the drugs widely applied in clinical treatment of diabetes mellitus mainly include insulin, insulin analogs, non-insulin oral hypoglycemic drugs and genetic drugs. Nevertheless, there is still no complete therapy strategy for diabetes mellitus management by far due to the intrinsic deficiencies of drugs and limits in administration routes such as the adverse reactions caused by long-term subcutaneous injection and various challenges in oral administration, such as enzymatic degradation, chemical instability and poor gastrointestinal absorption. Therefore, it is remarkably necessary to develop appropriate delivery systems and explore complete therapy strategies according to the characters of drugs and diabetes mellitus. Delivery systems have been found to be potentially beneficial in many aspects for effective diabetes treatment, such as improving the stability of drugs, overcoming different biological barriers in vivo to increase bioavailability, and acting as an intelligent automatized system to mimic endogenous insulin delivery and reduce the risk of hypoglycemia. This review aims to provide an overview related with the research advances, development trend of drug therapy and the application of delivery systems in the treatment diabetes mellitus, which could offer reference for the application of various drugs in the field of diabetes mellitus treatment.
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Affiliation(s)
- Ruichen Zhao
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhiguo Lu
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jun Yang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
| | - Liqun Zhang
- Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Yan Li
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
| | - Xin Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
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Johansson KS, Sonne DP, Knop FK, Christensen MB. What is on the horizon for type 2 diabetes pharmacotherapy? – An overview of the antidiabetic drug development pipeline. Expert Opin Drug Discov 2020; 15:1253-1265. [DOI: 10.1080/17460441.2020.1791078] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Karl Sebastian Johansson
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - David Peick Sonne
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Filip Krag Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel Bring Christensen
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Müller-Wieland D, Schütt K, Brandts J, Marx N. [New oral antidiabetic drugs]. Herz 2020; 45:493-503. [PMID: 32601754 DOI: 10.1007/s00059-020-04946-8] [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: 10/24/2022]
Abstract
A paradigm change in the treatment of type 2 diabetes has recently emerged due to the introduction of new oral antidiabetic agents. Cardiovascular endpoint studies confirmed the safety of dipeptidyl peptidase 4 (DPP-4) inhibitors and a cardiovascular protective effect for glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose linked transporter 2 (SGLT-2) inhibitors. Furthermore, SGLT‑2 inhibitors reduce the risk for heart failure and have a renoprotective effect. These studies led to changes in clinical recommendations and guidelines. In patients with high or very high cardiorenal risk, SGLT‑2 inhibitors or GLP‑1 receptor agonists are recommended for risk protection independent of HbA1c values, with existing or high risk for chronic heart failure SGLT‑2 inhibitors are the preferred choice. Therefore, the choice of antidiabetic treatment strategy is no longer determined by the level of glycosylated hemoglobin (HbA1c) alone but particularly by the cardiorenal risk of the individual patient.
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Affiliation(s)
- Dirk Müller-Wieland
- Medizinische Klinik I, Universitätsklinikum RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Deutschland.
| | - Katharina Schütt
- Medizinische Klinik I, Universitätsklinikum RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Deutschland
| | - Julia Brandts
- Medizinische Klinik I, Universitätsklinikum RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Deutschland
| | - Nikolaus Marx
- Medizinische Klinik I, Universitätsklinikum RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Deutschland
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Shin Y, Moon JH, Chin HJ, Ferrannini E, Lim S. Glycemic Efficacy and Metabolic Consequences of an Empagliflozin Add-on versus Conventional Dose-Increasing Strategy in Patients with Type 2 Diabetes Inadequately Controlled by Metformin and Sulfonylurea. Endocrinol Metab (Seoul) 2020; 35:329-338. [PMID: 32615717 PMCID: PMC7386128 DOI: 10.3803/enm.2020.35.2.329] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 04/07/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND We assessed the glucose-lowering efficacy of adding empagliflozin versus dose escalating existing medications in patients with uncontrolled type 2 diabetes (T2D). METHODS This was a 6-month retrospective case-control study in subjects with uncontrolled T2D (glycated hemoglobin [HbA1c] >7%) on conventional treatment. The study group started add-on therapy with empagliflozin (10 mg once a day) while the control group was up-titrated with existing medication, using either monotherapy or a combination of metformin, sulfonylurea, and a dipeptidyl peptidase-4 inhibitor. The primary endpoints included changes in HbA1c, fasting plasma glucose (FPG), and 2-hour postprandial glucose (PP2) levels. Secondary outcomes included changes in body composition, body mass index (BMI), and serum ketone bodies, and urinary excretion of sodium, potassium, chlorine, calcium, phosphorus, and glucose. RESULTS After treatment, the reduction in HbA1c was significantly greater in the empagliflozin group than in controls (from 8.6%±1.6% to 7.6%±1.5% vs. 8.5%±1.1% to 8.1%±1.1%; P<0.01). Similar patterns were found in FPG and PP2 levels. Empagliflozin decreased systolic and diastolic blood pressure, triglycerides, and alanine and aspartate aminotransferase levels. Body weight, BMI, waist circumference, fat mass, and abdominal visceral fat area decreased significantly while lean body mass was maintained. Total ketones, β-hydroxybutyrate, and acetoacetate levels increased significantly after empagliflozin. CONCLUSION In addition to glucose lowering, an empagliflozin add-on regimen decreased blood pressure and body fat, and improved metabolic profiles significantly. Empagliflozin add-on is superior to dose escalation in patients with T2D who have inadequate glycemic control on standard medications.
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Affiliation(s)
- Yujin Shin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam,
Korea
| | - Ji Hye Moon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam,
Korea
| | - Ho Jun Chin
- Division of Nephrology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam,
Korea
| | | | - Soo Lim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam,
Korea
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Abstract
Diabetic ketoacidosis (DKA) is the most common acute hyperglycaemic emergency in people with diabetes mellitus. A diagnosis of DKA is confirmed when all of the three criteria are present - 'D', either elevated blood glucose levels or a family history of diabetes mellitus; 'K', the presence of high urinary or blood ketoacids; and 'A', a high anion gap metabolic acidosis. Early diagnosis and management are paramount to improve patient outcomes. The mainstays of treatment include restoration of circulating volume, insulin therapy, electrolyte replacement and treatment of any underlying precipitating event. Without optimal treatment, DKA remains a condition with appreciable, although largely preventable, morbidity and mortality. In this Primer, we discuss the epidemiology, pathogenesis, risk factors and diagnosis of DKA and provide practical recommendations for the management of DKA in adults and children.
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Affiliation(s)
- Ketan K Dhatariya
- Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospitals NHS Foundation Trust, Colney Lane, Norwich, Norfolk, UK.,Norwich Medical School, University of East Anglia, Norfolk, UK
| | - Nicole S Glaser
- Department of Pediatrics, University of California Davis, School of Medicine, Sacramento, CA, USA
| | - Ethel Codner
- Institute of Maternal and Child Research, School of Medicine, University of Chile, Santiago, Chile
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Saponaro C, Mühlemann M, Acosta-Montalvo A, Piron A, Gmyr V, Delalleau N, Moerman E, Thévenet J, Pasquetti G, Coddeville A, Cnop M, Kerr-Conte J, Staels B, Pattou F, Bonner C. Interindividual Heterogeneity of SGLT2 Expression and Function in Human Pancreatic Islets. Diabetes 2020; 69:902-914. [PMID: 31896553 DOI: 10.2337/db19-0888] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 12/27/2019] [Indexed: 11/13/2022]
Abstract
Studies implicating sodium-glucose cotransporter 2 (SGLT2) inhibitors in glucagon secretion by pancreatic α-cells reported controversial results. We hypothesized that interindividual heterogeneity in SGLT2 expression and regulation may affect glucagon secretion by human α-cells in response to SGLT2 inhibitors. An unbiased RNA-sequencing analysis of 207 donors revealed an unprecedented level of heterogeneity of SLC5A2 expression. To determine heterogeneity of SGLT2 expression at the protein level, the anti-SGLT2 antibody was first rigorously evaluated for specificity, followed by Western blot and immunofluorescence analysis on islets from 10 and 12 donors, respectively. The results revealed a high interdonor variability of SGLT2 protein expression. Quantitative analysis of 665 human islets showed a significant SGLT2 protein colocalization with glucagon but not with insulin or somatostatin. Moreover, glucagon secretion by islets from 31 donors at low glucose (1 mmol/L) was also heterogeneous and correlated with dapagliflozin-induced glucagon secretion at 6 mmol/L glucose. Intriguingly, islets from three donors did not secrete glucagon in response to either 1 mmol/L glucose or dapagliflozin, indicating a functional impairment of the islets of these donors to glucose sensing and SGLT2 inhibition. Collectively, these data suggest that heterogeneous expression of SGLT2 protein and variability in glucagon secretory responses contribute to interindividual differences in response to SGLT2 inhibitors.
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Affiliation(s)
- Chiara Saponaro
- INSERM, U1190, Lille, France
- European Genomic Institute for Diabetes, Lille, France
- University of Lille, Lille, France
| | - Markus Mühlemann
- INSERM, U1190, Lille, France
- European Genomic Institute for Diabetes, Lille, France
- University of Lille, Lille, France
| | - Ana Acosta-Montalvo
- INSERM, U1190, Lille, France
- European Genomic Institute for Diabetes, Lille, France
- University of Lille, Lille, France
| | - Anthony Piron
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Valery Gmyr
- INSERM, U1190, Lille, France
- European Genomic Institute for Diabetes, Lille, France
- University of Lille, Lille, France
| | - Nathalie Delalleau
- INSERM, U1190, Lille, France
- European Genomic Institute for Diabetes, Lille, France
- University of Lille, Lille, France
| | - Ericka Moerman
- INSERM, U1190, Lille, France
- European Genomic Institute for Diabetes, Lille, France
- University of Lille, Lille, France
| | - Julien Thévenet
- INSERM, U1190, Lille, France
- European Genomic Institute for Diabetes, Lille, France
- University of Lille, Lille, France
| | - Gianni Pasquetti
- INSERM, U1190, Lille, France
- European Genomic Institute for Diabetes, Lille, France
- University of Lille, Lille, France
| | - Anais Coddeville
- INSERM, U1190, Lille, France
- European Genomic Institute for Diabetes, Lille, France
- University of Lille, Lille, France
| | - Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
- Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Julie Kerr-Conte
- INSERM, U1190, Lille, France
- European Genomic Institute for Diabetes, Lille, France
- University of Lille, Lille, France
| | - Bart Staels
- European Genomic Institute for Diabetes, Lille, France
- University of Lille, Lille, France
- INSERM, U1011, Lille, France
- Service Biochimie automatisée Pathologies des protéines, CHU Lille, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - François Pattou
- INSERM, U1190, Lille, France
- European Genomic Institute for Diabetes, Lille, France
- University of Lille, Lille, France
- Chirurgie Endocrinienne et Métabolique, CHU Lille, Lille, France
| | - Caroline Bonner
- INSERM, U1190, Lille, France
- European Genomic Institute for Diabetes, Lille, France
- University of Lille, Lille, France
- Institut Pasteur de Lille, Lille, France
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El Mouhayyar C, Riachy R, Khalil AB, Eid A, Azar S. SGLT2 Inhibitors, GLP-1 Agonists, and DPP-4 Inhibitors in Diabetes and Microvascular Complications: A Review. Int J Endocrinol 2020; 2020:1762164. [PMID: 32190049 PMCID: PMC7066394 DOI: 10.1155/2020/1762164] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 01/03/2020] [Indexed: 12/27/2022] Open
Abstract
The prevalence of diabetes and its associated complications is increasing throughout the decades. Promising diabetes medications were introduced to the market including GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors aiming to target these complications. The literature lacks sufficient data regarding these new medications and their influence on nephropathy, retinopathy, and neuropathy. This review expands on the major results of effects of the 3 drug classes on microvascular complications. In our review, both SGLT2 inhibitors and GLP-1 agonists appear to have promising nephroprotective outcomes at this stage, with less promising outcomes seen with DPP-4 inhibitors. Moreover, the retinoprotective outcomes of both SGLT2 inhibitors and DPP-4 inhibitors were only tested on mice, while those of GLP-1 agonists were assessed in few trials. In addition, the results of both GLP-1 agonists and DPP-4 inhibitors showed discrepancies in these studies. On the contrary, conclusions regarding the effect of these medications on neuroprotective outcomes cannot be drawn at the time due to the lack of clinical trials targeting these complications. Hence, a clearer picture of the microvascular outcomes will manifest over time with the release of multiple upcoming clinical trials.
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Affiliation(s)
- Christopher El Mouhayyar
- Department of Anatomy, Cell Biology and Physiology, American University of Beirut, Beirut, Lebanon
- Diabetes Program, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Ruba Riachy
- Diabetes Program, American University of Beirut-Medical Center, Beirut, Lebanon
- Department of Internal Medicine, Division of Endocrinology and Diabetes, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Abir Bou Khalil
- Diabetes Program, American University of Beirut-Medical Center, Beirut, Lebanon
- Department of Internal Medicine, Division of Endocrinology and Diabetes, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Asaad Eid
- Department of Anatomy, Cell Biology and Physiology, American University of Beirut, Beirut, Lebanon
- Diabetes Program, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Sami Azar
- Diabetes Program, American University of Beirut-Medical Center, Beirut, Lebanon
- Department of Internal Medicine, Division of Endocrinology and Diabetes, American University of Beirut-Medical Center, Beirut, Lebanon
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Sumathi A, Meganathan S. Semi supervised data mining model for the prognosis of pre-diabetic conditions in type 2 Diabetes Mellitus. Bioinformation 2019; 15:875-882. [PMID: 32256007 PMCID: PMC7088425 DOI: 10.6026/97320630015875] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 12/26/2019] [Accepted: 12/29/2019] [Indexed: 02/07/2023] Open
Abstract
Diabetic Mellitus is the leading disease in the world irrespective of age and geographical location. It is estimated that 43% of the overall population is affected by the disease. The reasons for the disease include inappropriate diet lifestyle with allied symptoms like obesity. Therefore, the prognosis and diagnosis of the disease are important for adequate combat and care. The prognosis related known symptoms of the disease include incontinence (inability to control urination) and frequent fatigue. Moreover, early prediction of the disease plays an important role in the prognosis of other associated conditions such as heart failure leading to chronic illness. Hence, it is of interest to describe a data mining based prediction model using known features (derived from epidemiological data collected from the public hospital using routine tests) to help in the prognosis of the disease. We used data pre-processing techniques for handling missing values and dimensionality reduction models to improve data quality. The Minimum Description Length principle (MDL) model for discretization (replacing a continuum with a finite set of points) is used to reduce high-level dimensionality of the dataset, which enabled to categorize the dataset into small groups in ordered intervals. Thus, we describe a semi-supervised learning technique (identifies promising attributes using clustering and classification methods) by combining data mining techniques for reasonable accuracy having adequate sensitivity and specificity for further discussion, cross-validation, revaluation, and application. Early prediction of the disease with improved accuracy by analysing specificity ranges in blood pressure and glucose levels will be useful to combat Diabetes Mellitus.
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Affiliation(s)
- A Sumathi
- Department of Computer Science Engineering, SASTRA Deemed To be University, Srinivasa Ramanujan Centre (SRC), Kumbakonam, Tamil Nadu, India
| | - S Meganathan
- Department of Computer Science Engineering, SASTRA Deemed To be University, Srinivasa Ramanujan Centre (SRC), Kumbakonam, Tamil Nadu, India
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Lankatillake C, Huynh T, Dias DA. Understanding glycaemic control and current approaches for screening antidiabetic natural products from evidence-based medicinal plants. PLANT METHODS 2019; 15:105. [PMID: 31516543 PMCID: PMC6731622 DOI: 10.1186/s13007-019-0487-8] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 08/20/2019] [Indexed: 05/15/2023]
Abstract
Type 2 Diabetes Mellitus has reached epidemic proportions as a result of over-nutrition and increasingly sedentary lifestyles. Current therapies, although effective, are not without limitations. These limitations, the alarming increase in the prevalence of diabetes, and the soaring cost of managing diabetes and its complications underscores an urgent need for safer, more efficient and affordable alternative treatments. Over 1200 plant species are reported in ethnomedicine for treating diabetes and these represents an important and promising source for the identification of novel antidiabetic compounds. Evaluating medicinal plants for desirable bioactivity goes hand-in-hand with methods in analytical biochemistry for separating and identifying lead compounds. This review aims to provide a comprehensive summary of current methods used in antidiabetic plant research to form a useful resource for researchers beginning in the field. The review summarises the current understanding of blood glucose regulation and the general mechanisms of action of current antidiabetic medications, and combines knowledge on common experimental approaches for screening plant extracts for antidiabetic activity and currently available analytical methods and technologies for the separation and identification of bioactive natural products. Common in vivo animal models, in vitro models, in silico methods and biochemical assays used for testing the antidiabetic effects of plants are discussed with a particular emphasis on in vitro methods such as cell-based bioassays for screening insulin secretagogues and insulinomimetics. Enzyme inhibition assays and molecular docking are also highlighted. The role of metabolomics, metabolite profiling, and dereplication of data for the high-throughput discovery of novel antidiabetic agents is reviewed. Finally, this review also summarises sample preparation techniques such as liquid-liquid extraction, solid phase extraction, and supercritical fluid extraction, and the critical function of nuclear magnetic resonance and high resolution liquid chromatography-mass spectrometry for the dereplication, putative identification and structure elucidation of natural compounds from evidence-based medicinal plants.
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Affiliation(s)
- Chintha Lankatillake
- School of Health and Biomedical Sciences, Discipline of Laboratory Medicine, RMIT University, Bundoora, 3083 Australia
| | - Tien Huynh
- School of Science, RMIT University, Bundoora, VIC 3083 Australia
| | - Daniel A. Dias
- School of Health and Biomedical Sciences, Discipline of Laboratory Medicine, RMIT University, Bundoora, 3083 Australia
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Kuriyama S. A Potential Mechanism of Cardio-Renal Protection with Sodium-Glucose Cotransporter 2 Inhibitors: Amelioration of Renal Congestion. Kidney Blood Press Res 2019; 44:449-456. [DOI: 10.1159/000501081] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 05/18/2019] [Indexed: 11/19/2022] Open
Abstract
Background: This review considers anew the etiology of the cardio-renal protective effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors by extending the discussion to renal congestion, inherent in diabetic kidney disease (DKD) even at an early stage of nephropathy in which heart failure (HF) or salt and water accumulation is asymptomatic. Summary: The interstitial fluid (IF) space of the kidney space plays a crucial role for tubulointerstitial inflammation, renal hypoxia, and ischemic injury, which often leads to renal progression. In DKD, as a result of hyperglycemic milieu, excessive salt and water can be accumulated in the IF space, creating renal congestion. I hypothesize that SGLT2 inhibitors cause a shift in extracellular water from the IF space to the intravascular space to compensate for the SGLT2 inhibitor-induced hypovolemia. This decrease in IF volume ameliorates the IF space milieu and may reduce inflammation, hypoxia, and ischemic injury. Message: The present review proposes a novel theory; unlike other hypoglycemic agents or diuretics, SGLT2 inhibitor could protect DKD from failing by improving latent renal congestion even without symptomatic HF.
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Katsiki N, Dimitriadis G, Hahalis G, Papanas N, Tentolouris N, Triposkiadis F, Tsimihodimos V, Tsioufis C, Mikhailidis DP, Mantzoros C. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) use and risk of amputation: an expert panel overview of the evidence. Metabolism 2019; 96:92-100. [PMID: 30980838 DOI: 10.1016/j.metabol.2019.04.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 04/03/2019] [Accepted: 04/06/2019] [Indexed: 12/12/2022]
Abstract
Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are oral antidiabetic agents that exert their glucose-lowering effect by increasing renal excretion of glucose. These drugs have been reported to beneficially affect cardiovascular (CV) and renal outcomes. However, concerns have recently been raised in relation to increased risk of lower-extremities amputation with canagliflozin and it remains unclear whether and to what extent this side effect could also occur with other SGLT2i. The present expert panel overview focuses on the three SGLT2i available and widely used in the US and Europe, i.e. empagliflozin, canagliflozin and dapagliflozin and only refers briefly to other SGLT2i for which less data are available. The results of large CV outcome trials with these SGLT2i are presented, focusing specifically on the data in relation to amputation risk. The potential pathophysiological mechanisms involved in this side effect are discussed. Furthermore, available data reporting amputation cases in SGLT2i users are critically reviewed. The expert panel concludes that, based on current data, increased amputation risk seems to be related only to canagliflozin, thus representing a drug-effect rather than a SGLT2i class-effect. The exact pathways underlying this drug-induced adverse event, possibly related to off-target drug effects rather than SGLT2 inhibition per se, should be elucidated in future studies. Continuous monitoring and pharmacovigilance is necessary and head to head trials would also be essential to provide definitive conclusions.
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Affiliation(s)
- Niki Katsiki
- First Department of Internal Medicine, Division of Endocrinology and Metabolism, Diabetes Center, Medical School, AHEPA University Hospital, Thessaloniki, Greece.
| | - George Dimitriadis
- 2nd Department of Internal Medicine, Research Institute and Diabetes Center, "Attikon" University hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - George Hahalis
- Department of Cardiology, University of Patras Medical School, Patras, Greece
| | - Nikolaos Papanas
- Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece
| | - Nikolaos Tentolouris
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | | | - Vasilios Tsimihodimos
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece
| | - Costas Tsioufis
- First Cardiology Clinic, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens, Greece
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Campus, University College London Medical School, University College London (UCL), London, UK.
| | - Christos Mantzoros
- Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
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Abstract
Diabetes mellitus is an important comorbidity in patients with heart failure. The presence of heart failure in diabetes worsens the prognosis of patients. Recent studies suggest that appropriate diagnostic approaches followed by differential medical treatment are of crucial importance to improve patient outcomes. This article summarizes important aspects of the association between diabetes mellitus and heart failure.
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Mori M, Higuchi K. [The senescence-accelerated mouse as a model for geriatrics and aging biology]. Nihon Yakurigaku Zasshi 2019; 153:179-185. [PMID: 30971658 DOI: 10.1254/fpj.153.179] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Rapid expansion of aged population is predicted worldwide. To cope with problems expected from this situation and extend the period of active and healthy life of people as much as possible, it is important to elucidate not only the biological mechanisms of "aging", but also the etiology of various "age-related diseases". To attain this goal, extensive studies using excellent animal models are indispensable. Senescence-accelerated mouse (SAM) is a series of inbred mouse strains that includes SAMP1, SAMP6, SAMP8, SAMP10, and SAMR1. SAMP strains exhibit accelerated senescence and short lifespan. In addition, each strain shows specific age-related disease phenotypes which are similar to symptoms observed in humans, such as senile amyloidosis (SAMP1), senile osteoporosis (SAMP6), and age-dependent deficits in learning and memory (SAMP8), making SAM mice useful for an aging research. In this review, we introduce the characteristics and application of SAM in geriatrics and aging biology.
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Affiliation(s)
- Masayuki Mori
- Department of Advanced Medicine for Health Promotion, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University
| | - Keiichi Higuchi
- Department of Biological Sciences for Intractable Neurological Diseases, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University
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Affiliation(s)
- Sally M Marshall
- Diabetes Research Group, Institute of Cellular Medicine, Faculty of Clinical Medical Sciences, Newcastle University, 4th Floor William Leech Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
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