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Akunjee MM, Khosla SG, Nylen ES, Sen S. SGLT2 inhibitors use in kidney disease: what did we learn? Am J Physiol Endocrinol Metab 2025; 328:E856-E868. [PMID: 40279256 DOI: 10.1152/ajpendo.00034.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 03/26/2025] [Accepted: 04/18/2025] [Indexed: 04/27/2025]
Abstract
Chronic kidney disease (CKD) increases the risk for cardiovascular morbidity and mortality and it's prevalence continues to rise throughout the world. Newer, more efficacious therapies, slow progression of CKD, decrease long-term sequela like end-stage kidney disease (ESKD) and cardiovascular events, improving survival. Postmarketing cardiovascular outcome trials (CVOT) have demonstrated improved cardiovascular outcomes with the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) like canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin in patients with type 2 diabetes mellitus (T2DM), Similarly, secondary analysis of CVOT and renal outcome trials with the use of SGLT2i in patients without T2DM showed improved renal function and albuminuria. In these studies, nondiabetic CKD was defined as an estimated glomerular filtration rate (eGFR) of 20-75 mL/min/1.73 m2 with albuminuria ranging from 200 to 5,000 mg/g in the absence of diabetes. As a class effect, in addition to modulation of hemodynamic and metabolic activities, SGLT2i exert renal protection by suppressing inflammation and fibrosis. We conducted an extensive search in the PubMed database for original papers published from 2009 through 2024 using keywords such as nondiabetic kidney disease, diabetic kidney disease, SGLT2i, and kidney outcomes. Based on our research of published literature, we present a review and propose, consideration of SGLT2i in nondiabetic kidney disease for long-term cardiovascular and renal benefit (Dharia A, Khan A, Sridhar VS, Cherney DZI. Annu Rev Med 74: 369-384, 2023). We will highlight relevant translational studies to propose a possible cell-based mechanism for cardiovascular benefits noted secondary to use of SGLT2i.
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Affiliation(s)
- Munaza M Akunjee
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
| | - Shikha G Khosla
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
| | - Eric S Nylen
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
| | - Sabyasachi Sen
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
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Rastogi A, Chertow GM, Collins A, Kelepouris E, Kotzker W, Middleton JP, Rajpal M, Roy-Chaudhury P. Utilization of Potassium Binders for the Management of Hyperkalemia in Chronic Kidney Disease: A Position Statement by US Nephrologists. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:514-522. [PMID: 39577885 DOI: 10.1053/j.akdh.2024.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 08/02/2024] [Indexed: 11/24/2024]
Abstract
Two potassium (K+) binders-patiromer sorbitex calcium and sodium zirconium cyclosilicate-are recommended by international guidelines for the management of hyperkalemia. There is, however, no universally accepted best practice for how to appropriately utilize K+ binders in the long-term clinical management of CKD. A panel of eight US-based nephrologists convened in October 2022 to develop a consensus statement regarding utilizing K+ binders in clinical practice to help manage patients with nonemergent, persistent/recurrent hyperkalemia in CKD. Consensus was reached on the following topics: (1) identifying risk factors for hyperkalemia; (2) serum K+ monitoring before and during K+ binder use; (3) utilizing K+ binders in patients receiving renin-angiotensin-aldosterone system inhibitors and dialysis; and (4) when to initiate K+ binders and their duration of use. These consensus statements for the use of K+ binders may assist the nephrology community in optimizing management of hyperkalemia in patients across the spectrum of CKD.
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Affiliation(s)
- Anjay Rastogi
- Department of Medicine, David Geffen School of Medicine at UCLA Los Angeles, Los Angeles, CA
| | - Glenn M Chertow
- Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Ashté Collins
- Division of Renal Diseases and Hypertension, George Washington University School of Medicine, Washington, DC
| | - Ellie Kelepouris
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | | | - John P Middleton
- Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, NC
| | | | - Prabir Roy-Chaudhury
- Division of Nephrology, Department of Medicine, University of North Carolina Kidney Center, Chapel Hill, NC and the WG (Bill) Hefner Salisbury VA Medical Center, Salisbury, NC.
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Qu P, Li L, Jin Q, Liu D, Qiao Y, Zhang Y, Sun Q, Ran S, Li Z, Liu T, Peng L. Histone methylation modification and diabetic kidney disease: Potential molecular mechanisms and therapeutic approaches (Review). Int J Mol Med 2024; 54:104. [PMID: 39301658 DOI: 10.3892/ijmm.2024.5428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 08/26/2024] [Indexed: 09/22/2024] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end‑stage renal disease, and is characterized by persistent proteinuria and decreased glomerular filtration rate. Despite extensive efforts, the increasing incidence highlights the urgent need for more effective treatments. Histone methylation is a crucial epigenetic modification, and its alteration can destabilize chromatin structure, thereby regulating the transcriptional activity of specific genes. Histone methylation serves a substantial role in the onset and progression of various diseases. In patients with DKD, changes in histone methylation are pivotal in mediating the interactions between genetic and environmental factors. Targeting these modifications shows promise in ameliorating renal histological manifestations, tissue fibrosis and proteinuria, and represents a novel therapeutic frontier with the potential to halt DKD progression. The present review focuses on the alterations in histone methylation during the development of DKD, systematically summarizes its impact on various renal parenchymal cells and underscores the potential of targeted histone methylation modifications in improving DKD outcomes.
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Affiliation(s)
- Peng Qu
- Institute of Clinical Medical Sciences, China‑Japan Friendship Hospital, Beijing 100029, P.R. China
| | - Lanfang Li
- Institute of Clinical Medical Sciences, China‑Japan Friendship Hospital, Beijing 100029, P.R. China
| | - Qi Jin
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100029, P.R. China
| | - Donghai Liu
- China‑Japan Friendship Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100029, P.R. China
| | - Yuan Qiao
- China‑Japan Friendship Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100029, P.R. China
| | - Yijia Zhang
- Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, P.R. China
| | - Qiuyue Sun
- Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing 100029, P.R. China
| | - Shuman Ran
- Institute of Clinical Medical Sciences, China‑Japan Friendship Hospital, Beijing 100029, P.R. China
| | - Zecheng Li
- Institute of Clinical Medical Sciences, China‑Japan Friendship Hospital, Beijing 100029, P.R. China
| | - Tongtong Liu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100029, P.R. China
| | - Liang Peng
- Institute of Clinical Medical Sciences, China‑Japan Friendship Hospital, Beijing 100029, P.R. China
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Chang J, Wang J, Li X, Zhong Y. Predicting prospective therapeutic targets of Bombyx batryticatus for managing diabetic kidney disease through network pharmacology analysis. Medicine (Baltimore) 2024; 103:e39598. [PMID: 39287308 PMCID: PMC11404872 DOI: 10.1097/md.0000000000039598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 05/17/2024] [Accepted: 08/15/2024] [Indexed: 09/19/2024] Open
Abstract
We conducted network pharmacology and molecular docking analyses, and executed in vitro experiments to assess the mechanisms and prospective targets associated with the bioactive components of Bombyx batryticatus in the treatment of diabetic kidney disease (DKD). The bioactive components and potential targets of B batryticatus were sourced from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. Using 5 disease databases, we conducted a comprehensive screening of potential disease targets specifically associated with DKD. Common targets shared between the bioactive components and disease targets were identified through the use of the R package, and subsequently, a protein-protein interaction network was established using data from the STRING database. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses pertaining to the identified common targets were conducted using the Database for Annotation, Visualization, and Integrated Discovery. Molecular docking simulations involving the bioactive components and their corresponding targets were modeled through AutoDock Vina and Pymol. Finally, to corroborate and validate these findings, experimental assays at the cellular level were conducted. Six bioactive compounds and 142 associated targets were identified for B batryticatus. Among the 796 disease targets associated with DKD, 56 targets were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed the involvement of these shared targets in diverse biological processes and signaling pathways, notably the PI3K-Akt signaling pathway. Molecular docking analyses indicated a favorable binding interaction between quercetin, the principal bioactive compound in B batryticatus, and RAC-alpha serine/threonine-protein kinase. Subsequently, in vitro experiments substantiated the inhibitory effect of quercetin on the phosphorylation level of PI3K and Akt. The present study provides theoretical evidence for a comprehensive exploration of the mechanisms and molecular targets by which B batryticatus imparts protective effects against DKD.
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Affiliation(s)
- Jingsheng Chang
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jue Wang
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xueling Li
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yifei Zhong
- Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Mendez Espinoza I, Choos END, Ecelbarger CM, Shepard BD. SGLT2 inhibition leads to a restoration of hepatic and circulating metabolites involved in the folate cycle and pyrimidine biosynthesis. Am J Physiol Gastrointest Liver Physiol 2024; 327:G235-G253. [PMID: 38915277 PMCID: PMC11427092 DOI: 10.1152/ajpgi.00029.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 06/19/2024] [Accepted: 06/19/2024] [Indexed: 06/26/2024]
Abstract
Inhibition of sodium-glucose cotransporter 2 (SGLT2) by empagliflozin (EMPA) and other "flozins" can improve glycemic control under conditions of diabetes and kidney disease. Though they act on the kidney, they also offer cardiovascular and liver protection. Previously, we found that EMPA decreased circulating triglycerides and hepatic lipid and cholesterol esters in male TallyHo mice fed a high-milk-fat diet (HMFD). The goal of this study was to determine whether the liver protection is associated with a change in metabolic function by characterizing the hepatic and circulating metabolic and lipidomic profiles using targeted LC-MS. In both male and female mice, HMFD feeding significantly altered the circulating and hepatic metabolome compared with low-fat diet (LFD). Addition of EMPA resulted in the restoration of circulating orotate (intermediate in pyrimidine biosynthesis) and hepatic dihydrofolate (intermediate in the folate and methionine cycles) levels in males and acylcarnitines in females. These changes were partially explained by altered expression of rate-limiting enzymes in these pathways. This metabolic signature was not detected when EMPA was incorporated into an LFD, suggesting that the restoration requires the metabolic shift that accompanies the HMFD. Notably, the HMFD increased expression of 18 of 20 circulating amino acids in males and 11 of 20 in females, and this pattern was reversed by EMPA. Finally, we confirmed that SGLT2 inhibition upregulates ketone bodies including β-hydroxybutyrate. Collectively, this study highlights the metabolic changes that occur with EMPA treatment, and sheds light on the possible mechanisms by which this drug offers liver and systemic protection.NEW & NOTEWORTHY Sodium-glucose cotransporter 2 (SGLT2) inhibitors, including empagliflozin, have emerged as a new treatment option for individuals with type 2 diabetes that have positive impacts on kidney and cardiovascular disease. However, less is known about their impact on other tissues, including the liver. Here, we report that empagliflozin reduces hepatic steatosis that is associated with restoring metabolic intermediates in the folate and pyrimidine biosynthesis pathways. These changes may lead to new approaches to treat nonalcoholic fatty liver disease.
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Affiliation(s)
- Ileana Mendez Espinoza
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Elijah N D Choos
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Carolyn M Ecelbarger
- Department of Medicine, Georgetown University, Washington, District of Columbia, United States
| | - Blythe D Shepard
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
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Chong KS, Chang YH, Lin MH, Hsu CN, Wang CC, Wang CY, Huang YL, Lin FJ, Ou HT. Kidney outcomes with SGLT2is for type 2 diabetes patients: does background treatment with metformin or RASis matter? Front Endocrinol (Lausanne) 2024; 15:1329945. [PMID: 38994012 PMCID: PMC11236716 DOI: 10.3389/fendo.2024.1329945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 06/10/2024] [Indexed: 07/13/2024] Open
Abstract
Introduction There is a lack of real-world evidence regarding the impact of concomitant metformin and renin-angiotensin system inhibitors (RASis) on sodium-glucose cotransporter-2 inhibitor (SGLT2i)-associated kidney outcomes. This study was aimed to investigate whether SGLT2i-associated kidney outcomes were modified by the concomitant use of metformin or RASis in patients with type 2 diabetes. Methods SGLT2i users were identified from three electronic health record databases during May 2016 and December 2017 and categorized into those with and without concomitant use of metformin or RASis. Propensity score matching was performed to minimize baseline differences between groups. Study outcomes were mean estimated glomerular filtration rate (eGFR) change and time to 30%, 40%, and 50% eGFR reductions. A meta-analysis was performed to combine the estimates across databases. Results After matching, there were 6,625 and 3,260 SGLT2i users with and without metformin, and 6,654 and 2,746 SGLT2i users with and without RASis, respectively. The eGFR dip was similar in SGLT2i users with and without metformin therapy, but was greater in SGLT2i users with RASis compared to those without RASis. Neither metformin nor RASi use had a significant effect on SGLT2i-associated eGFR reductions, as evidenced by the hazard ratios (95% CIs) of 30% eGFR reductions for SGLT2is with versus without metformin/RASis, namely 1.02 (0.87-1.20)/1.09 (0.92-1.31). Such findings were also observed in the outcomes of 40% and 50% eGFR reductions. Conclusion Using metformin or RASis did not modify SGLT2i-associated kidney outcomes in type 2 diabetes.
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Affiliation(s)
- Kah Suan Chong
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Hsin Chang
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Meng-Hsuan Lin
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chien-Ning Hsu
- Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chi-Chuan Wang
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
- Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan
| | - Chih-Yuan Wang
- College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yun-Lin Huang
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Fang-Ju Lin
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
- Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan
| | - Huang-Tz Ou
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Iordan L, Gaita L, Timar R, Avram V, Sturza A, Timar B. The Renoprotective Mechanisms of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i)-A Narrative Review. Int J Mol Sci 2024; 25:7057. [PMID: 39000165 PMCID: PMC11241663 DOI: 10.3390/ijms25137057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Chronic kidney disease (CKD) is a noncommunicable condition that has become a major healthcare burden across the globe, often underdiagnosed and associated with low awareness. The main cause that leads to the development of renal impairment is diabetes mellitus and, in contrast to other chronic complications such as retinopathy or neuropathy, it has been suggested that intensive glycemic control is not sufficient in preventing the development of diabetic kidney disease. Nevertheless, a novel class of antidiabetic agents, the sodium-glucose cotransporter-2 inhibitors (SGLT2i), have shown multiple renoprotective properties that range from metabolic and hemodynamic to direct renal effects, with a major impact on reducing the risk of occurrence and progression of CKD. Thus, this review aims to summarize current knowledge regarding the renoprotective mechanisms of SGLT2i and to offer a new perspective on this innovative class of antihyperglycemic drugs with proven pleiotropic beneficial effects that, after decades of no significant progress in the prevention and in delaying the decline of renal function, start a new era in the management of patients with CKD.
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Affiliation(s)
- Liana Iordan
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Laura Gaita
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Romulus Timar
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Vlad Avram
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Adrian Sturza
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Bogdan Timar
- “Pius Brinzeu” Emergency County Hospital, 300723 Timisoara, Romania; (L.I.); (R.T.); (V.A.); (A.S.); (B.T.)
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania
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Xie T, Zhao LJ. Synthetic approaches and clinical application of small-molecule inhibitors of sodium-dependent glucose transporters 2 for the treatment of type 2 diabetes mellitus. Eur J Med Chem 2024; 269:116343. [PMID: 38513341 DOI: 10.1016/j.ejmech.2024.116343] [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: 01/25/2024] [Revised: 03/08/2024] [Accepted: 03/15/2024] [Indexed: 03/23/2024]
Abstract
Sodium-dependent glucose transporters 2 (SGLT2) inhibitors are a class of small-molecule drugs that have gained significant attention in recent years for their potential clinical applications in the treatment of type 2 diabetes mellitus (T2DM). These inhibitors function by obstructing the kidneys' ability to reabsorb glucose, resulting in a rise in the excretion of glucose in urine (UGE) and subsequently lowering blood glucose levels. Several SGLT2 inhibitors, such as Dapagliflozin, Canagliflozin, and Empagliflozin, have been approved by regulatory authorities and are currently available for clinical use. These inhibitors have shown notable enhancements in managing blood sugar levels, reducing body weight, and lowering blood pressure in individuals with T2DM. Additionally, they have exhibited potential advantages in decreasing the likelihood of cardiovascular incidents and renal complications among this group of patients. This review article focuses on the synthesis and clinical application of small-molecule SGLT2 inhibitors, which have provided a new therapeutic approach for the management of T2DM.
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Affiliation(s)
- Tong Xie
- First People's Hospital of Shangqiu, Henan Province, Shangqiu, 476000, China.
| | - Li-Jie Zhao
- The Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, United States.
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Zhu X, Zhang C, Liu L, Xu L, Yao L. Senolytic combination of dasatinib and quercetin protects against diabetic kidney disease by activating autophagy to alleviate podocyte dedifferentiation via the Notch pathway. Int J Mol Med 2024; 53:26. [PMID: 38240118 PMCID: PMC10852012 DOI: 10.3892/ijmm.2024.5350] [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: 10/06/2023] [Accepted: 01/04/2024] [Indexed: 01/23/2024] Open
Abstract
The senolytics dasatinib and quercetin (DQ) alleviate age‑related disorders. However, limited information is available regarding the effects of DQ on diabetic kidney disease (DKD). The present study aimed to explore the effects of DQ on DKD and its potential molecular mechanism(s). Dasatinib (5 mg/kg) and quercetin (50 mg/kg) were administered to diabetic db/db mice by gavage for 20 weeks. Body weight, urine albumin‑creatinine ratio (ACR), serum creatinine (Scr), and blood urea nitrogen (BUN) were recorded at the indicated time periods. Periodic acid‑Schiff and Masson's staining were performed to assess the histopathological changes of kidney tissues. Immunohistochemical analysis, immunofluorescence and western blotting were performed to evaluate the expression levels of extracellular matrix (ECM) proteins, autophagic and podocyte differentiation‑related proteins. In addition, mouse podocytes were administered with high‑glucose, DQ and 3‑methyladenine (3‑MA), and the expression levels of autophagic and podocyte differentiation‑related proteins were measured. Moreover, following overexpression of the Notch intracellular domain (NICD), the expression levels of NICD, autophagic and podocyte differentiation‑related proteins were further assessed. DQ significantly reduced the body weight, blood glucose, ACR, Scr and BUN levels and improved the histopathological changes induced in diabetic db/db mice. In addition, DQ caused a significant downregulation of the expression levels of the ECM proteins, improved autophagy and induced an upregulation of the expression levels of podocyte differentiation‑related proteins. Administration of 3‑MA to mice significantly reduced podocyte differentiation, and overexpression of NICD could reverse the effects of DQ on autophagy and podocyte differentiation in vitro. The present study suggests that DQ protects against DKD by activation of autophagy to alleviate podocyte dedifferentiation via the Notch pathway.
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Affiliation(s)
- Xinwang Zhu
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Congxiao Zhang
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
- Blood Purification Center, The Fourth People's Hospital of Shenyang, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Linlin Liu
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Li Xu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524003, P.R. China
| | - Li Yao
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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Pan HC, Chen JY, Chen HY, Yeh FY, Huang TTM, Sun CY, Wang SI, Wei JCC, Wu VC. Sodium-Glucose Cotransport Protein 2 Inhibitors in Patients With Type 2 Diabetes and Acute Kidney Disease. JAMA Netw Open 2024; 7:e2350050. [PMID: 38170522 PMCID: PMC10765268 DOI: 10.1001/jamanetworkopen.2023.50050] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 11/13/2023] [Indexed: 01/05/2024] Open
Abstract
Importance Sodium-glucose cotransport protein 2 inhibitors (SGLT-2is) have demonstrated associations with positive kidney-related and cardiovascular outcomes in patients with type 2 diabetes. However, the association of SGLT-2is with outcomes among patients with type 2 diabetes and acute kidney disease (AKD) remains unclear. Objective To examine the long-term associations of SGLT-2is with mortality, major adverse kidney events (MAKEs), and major adverse cardiovascular events (MACEs) in patients with type 2 diabetes and AKD. Design, Setting, and Participants This cohort study used global health care data (the TriNetX database) spanning from September 30, 2002, to September 30, 2022. Propensity score matching was used to select a cohort of patients, and follow-up was conducted with a maximum duration of 5 years (completed on September 30, 2022) or until the occurrence of an outcome or death. Intervention The use of SGLT-2is. Main Outcomes and Measures The primary outcomes measured were mortality, MAKEs, and MACEs. Adjusted hazard ratios (AHR) with 95% CIs were calculated to compare the risks between SGLT-2i users and nonusers, representing the mean treatment effect among the treated patients. Results A total of 230 366 patients with AKD (mean [SD] age, 67.1 [16.4] years; 51.8% men and 48.2% women) were enrolled in the study, which had a median follow-up duration of 2.3 (IQR, 1.2-3.5) years. Among these, 5319 individuals (2.3%) were identified as SGLT-2i users. Among nonusers, the incidence of mortality was 18.7%, the incidence of MAKEs was 21.0%, and the incidence of MACEs was 25.8%. After propensity score matching, the absolute differences between SGLT-2i users and nonusers for incidence of mortality, MAKEs, and MACEs were 9.7%, 11.5%, and 12.3%, respectively. Based on the treated population, SGLT-2i use was associated with a significantly lower risk of mortality (AHR, 0.69 [95% CI, 0.62-0.77]), MAKEs (AHR, 0.62 [95% CI, 0.56-0.69]), and MACEs (AHR, 0.75 [95% CI, 0.65-0.88]) compared with nonuse. External validation using a multicenter cohort data set of 1233 patients with AKD patients who were SGLT-2i users confirmed the observed beneficial outcomes. Notably, the risk reduction associated with SGLT-2is remained significant even among patients without hypertension, those with advanced chronic kidney disease, and those not receiving other hypoglycemic agents. Conclusions and Relevance In this cohort study of patients with type 2 diabetes and AKD, administration of SGLT-2is was associated with a significant reduction in all-cause mortality, MAKEs, and MACEs when compared with nonuse, underscoring the importance of SGLT-2is in care after acute kidney injury. These findings emphasize the potential benefits of SGLT-2is in managing AKD and mitigating the risks of major cardiovascular and kidney diseases.
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Affiliation(s)
- Heng-Chih Pan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei
- College of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
- Division of Nephrology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
- Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Jui-Yi Chen
- Division of Nephrology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
- Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Hsing-Yu Chen
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Chinese Internal Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Fang-Yu Yeh
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Thomas Tao-Min Huang
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- National Taiwan University Hospital Study Group of Acute Renal Failure and Taiwan Consortium for Acute Kidney Injury and Renal Diseases, Taipei, Taiwan
| | - Chiao-Yin Sun
- Division of Nephrology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Shiow-Ing Wang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | | | - Vin-Cent Wu
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- National Taiwan University Hospital Study Group of Acute Renal Failure and Taiwan Consortium for Acute Kidney Injury and Renal Diseases, Taipei, Taiwan
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11
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Xi W, Zhao X, Wang B, Zhu Y, Li H. A Review of the Mechanism of Bailing for Diabetic Nephropathy Based on ChatGPT and Network Pharmacology. Int J Clin Pract 2024; 2024. [DOI: 10.1155/2024/1432594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 07/20/2024] [Indexed: 01/04/2025] Open
Abstract
Diabetes nephropathy (DN) is increasingly recognized as a critical complication in individuals with diabetes and a significant contributor to end‐stage renal disease (ESRD). Bailing capsules, which contain fermented cordyceps mycelium, are commonly utilized in treating various kidney disorders, including DN in clinical practice. This review aims to comprehensively detail the pharmacologically active components of Bailing, its mechanisms of action, and its clinical usage. By employing network pharmacology, we delve into the possible pathways Bailing impacts DN treatment. Current studies suggest that Bailing’s efficacy in DN primarily involves mechanisms related to lipid and atherosclerosis, cancer pathways, and small‐cell lung cancer. Key active ingredients in Bailing that contribute to its therapeutic effects include arachidonic acid, linalyl acetate, β‐sitosterol, and CLR. Furthermore, for literature selection in this review, we integrated GPT‐4 with bias analysis coprocessing. This evaluation provides a foundational understanding and direction for future research into the use of Bailing as a novel treatment for DN.
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12
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Cumhur Cure M, Cure E. Why have SGLT2 Inhibitors Failed to Achieve the Desired Success in COVID-19? Curr Pharm Des 2024; 30:1149-1156. [PMID: 38566383 DOI: 10.2174/0113816128300162240322075423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 03/11/2024] [Accepted: 03/12/2024] [Indexed: 04/04/2024]
Abstract
The SARS-CoV-2 virus emerged towards the end of 2019 and caused a major worldwide pandemic lasting at least 2 years, causing a disease called COVID-19. SARS-CoV-2 caused a severe infection with direct cellular toxicity, stimulation of cytokine release, increased oxidative stress, disruption of endothelial structure, and thromboinflammation, as well as angiotensin-converting enzyme 2 (ACE2) down-regulation-mediated renin-angiotensin system (RAS) activation. In addition to glucosuria and natriuresis, sodium-glucose transport protein 2 (SGLT2) inhibitors (SGLT2i) cause weight loss, a decrease in glucose levels with an insulin-independent mechanism, an increase in erythropoietin levels and erythropoiesis, an increase in autophagy and lysosomal degradation, Na+/H+-changer inhibition, prevention of ischemia/reperfusion injury, oxidative stress and they have many positive effects such as reducing inflammation and improving vascular function. There was great anticipation for SGLT2i in treating patients with diabetes with COVID-19, but current data suggest they are not very effective. Moreover, there has been great confusion in the literature about the effects of SGLT2i on COVID-19 patients with diabetes . Various factors, including increased SGLT1 activity, lack of angiotensin receptor blocker co-administration, the potential for ketoacidosis, kidney injury, and disruptions in fluid and electrolyte levels, may have hindered SGLT2i's effectiveness against COVID-19. In addition, the duration of use of SGLT2i and their impact on erythropoiesis, blood viscosity, cholesterol levels, and vitamin D levels may also have played a role in their failure to treat the virus. This article aims to uncover the reasons for the confusion in the literature and to unravel why SGLT2i failed to succeed in COVID-19 based on some solid evidence as well as speculative and personal perspectives.
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Affiliation(s)
- Medine Cumhur Cure
- Medilab Laboratory and Imaging Center, Department of Biochemistry, Sisli, Istanbul, Turkey
| | - Erkan Cure
- Department of Internal Medicine, Beylikdüzü Medilife Hospital, Yakuplu Mh, Beylikduzu, Istanbul, Turkey
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13
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Pandey AK, Bhatt DL, Pandey A, Marx N, Cosentino F, Pandey A, Verma S. Mechanisms of benefits of sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction. Eur Heart J 2023; 44:3640-3651. [PMID: 37674356 DOI: 10.1093/eurheartj/ehad389] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 03/07/2023] [Accepted: 05/29/2023] [Indexed: 09/08/2023] Open
Abstract
For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to reduce the composite of heart failure hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials. While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents. The SGLT2 inhibitors have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and autophagic flux in addition to altering iron homeostasis, which may contribute to improved cardiac energetics and function. These agents also reduce epicardial adipose tissue and alter adipokine signalling, which may play a role in the reductions in inflammation and oxidative stress observed with SGLT2 inhibition. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized. Finally, SGLT2 inhibitors have been shown to reduce myofilament stiffness as well as extracellular matrix remodelling/fibrosis in the heart, improving diastolic function. The SGLT2 inhibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will likely become foundational in the therapy of HFpEF.
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Affiliation(s)
- Arjun K Pandey
- Michael G. DeGroote School of Medicine, McMaster University, 90 Main Street West, Hamilton, Ontario L8P 1H6, Canada
| | - Deepak L Bhatt
- Mount Sinai Heart, Icahn School of Medicine at Mount Sinai Health System, 1 Gustave L. Levy Place, New York, NY 10029, USA
| | - Avinash Pandey
- Department of Medicine, University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, Ontario K1Y 4W7, Canada
| | - Nikolaus Marx
- Department of Internal Medicine, University Hospital Aachen, RWTH Aachen University, Templergraben 55, 52062 Aachen, Germany
| | - Francesco Cosentino
- Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Norrbacka S1:02, Stockholm, SE 17177, Sweden
- Heart, Vascular and Neuro Theme, Department of Cardiology, Karolinska University Hospital, Anna Steckséns gata 41, 171 64 Solna, Sweden
| | - Ambarish Pandey
- Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
| | - Subodh Verma
- Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ON, Canada
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14
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Al Rashid S, Elango P, Rahman SZ. SGLT2 Inhibitors for Cardioprotection. Oman Med J 2023; 38:e521. [PMID: 37711978 PMCID: PMC10498357 DOI: 10.5001/omj.2023.128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 08/28/2023] [Indexed: 09/16/2023] Open
Affiliation(s)
- Sulthan Al Rashid
- Department of Pharmacology, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Chennai, India
| | - P. Elango
- Department of Pharmacology, Bhaarath Medical College and Hospital, Bharath Institute of Higher Education and Research, Chennai, India
| | - Syed Ziaur Rahman
- Department of Pharmacology, Jawaharlal Nehru Medical College Hospital, Aligarh Muslim University, Aligarh, India
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15
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Rastogi A, Weir MR. Multimodal efforts to slow the progression of chronic kidney disease in patients with type 2 diabetes mellitus. J Diabetes Complications 2023; 37:108515. [PMID: 37356235 DOI: 10.1016/j.jdiacomp.2023.108515] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/30/2023] [Accepted: 05/17/2023] [Indexed: 06/27/2023]
Abstract
In patients with chronic kidney disease (CKD) associated with type 2 diabetes mellitus (T2DM), slowing kidney disease progression is an important therapeutic goal. Many patients with T2DM and CKD also have cardiovascular (CV) comorbidities. Renin-angiotensin-aldosterone system inhibitors (RAASis), which include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), are drugs with known antihypertensive effects as well as CV and kidney protective effects in patients with CKD. Studies have shown that adding a sodium-glucose cotransporter-2 (SGLT2) inhibitor to ACEI or ARB therapy has additive benefits in terms of kidney and CV protection in patients with CKD (with/without T2DM). For patients with CKD associated with T2DM who have persistent albuminuria despite taking the maximum tolerated dose of a RAASi, adding a nonsteroidal mineralocorticoid receptor antagonist (finerenone) has demonstrated CV and kidney benefits in clinical trials. In this article, we review the use of ACEIs and ARBs for their kidney and CV protective effects when used alone or in combination with a drug with a different mechanism of action. From reviewing the available evidence, it seems clear that a multimodal drug effort is needed to achieve maximum kidney and CV protective effects for patients with CKD associated with T2DM.
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Affiliation(s)
- Anjay Rastogi
- David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America.
| | - Matthew R Weir
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States of America
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16
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Fang L, Li G, Ren J, Duan J, Dong J, Liu Z. Integrated analysis for treatment scheme of sodium-glucose cotransporter 2 inhibitors in patients with diabetic kidney disease: a real-world study. Sci Rep 2023; 13:5969. [PMID: 37045938 PMCID: PMC10097684 DOI: 10.1038/s41598-023-33211-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 04/09/2023] [Indexed: 04/14/2023] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are recommended for type 2 diabetes mellitus patients with impaired renal function, but the actual situation of SGLT2i using is unclear. Therefore, in this real-world study, we analyzed the treatment scheme and clinical characteristics of SGLT2i in patients with diabetic kidney disease (DKD). We included DKD patients hospitalized in the First Affiliated Hospital of Zhengzhou University from October 2017 to March 2020. The Apriori algorithm of association rules was used to analysis treatment scheme prescribing SGLT2i and other different combinations of hypoglycemic drugs. SGLT2i was used in 781 (12.3%) of 6336 DKD patients, both number and proportion of patients using SGLT2i increased from 2017 to 2020 (1.9% to 33%). Nighty-eight percent of all DKD patients using SGLT2i were combined with other glucose-lowering agents, and insulin, metformin and alpha-glucosidase inhibitors are most commonly used in combination with hypoglycemic drugs. Multivariate analysis showed that compared with non-SGLT2i group, patients using SGLT2i were associated with younger age, higher BMI, higher HbA1c, preserved kidney function, dyslipidemia and combined with ACEI/ARB and statins. In this real-world study, use of SGLT2i in DKD patients is still low. Most patients performed younger age and in the early stages of chronic kidney disease with poor glycemic control. Clinical inertia should be overcome to fully exert the cardiorenal protective effects of SGLT2 inhibitors, with attention to rational drug use.
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Affiliation(s)
- Li Fang
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
- Clinical Research Center of Big-Data, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangpu Li
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
- Clinical Research Center of Big-Data, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingjing Ren
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, Zhengzhou, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China
- Clinical Research Center of Big-Data, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiayu Duan
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China.
- Henan Province Research Center for Kidney Disease, Zhengzhou, China.
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China.
- Clinical Research Center of Big-Data, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Jiancheng Dong
- Clinical Research Center of Big-Data, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Zhangsuo Liu
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China.
- Henan Province Research Center for Kidney Disease, Zhengzhou, China.
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, China.
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17
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Kuang Z, Hou N, Kan C, Han F, Qiu H, Sun X. The protective effects of SGLT-2 inhibitors, GLP-1 receptor agonists, and RAAS blockers against renal injury in patients with type 2 diabetes. Int Urol Nephrol 2023; 55:617-629. [PMID: 36036316 DOI: 10.1007/s11255-022-03355-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 08/21/2022] [Indexed: 10/15/2022]
Abstract
Diabetic kidney disease is one of the most severe complications of type 2 diabetes mellitus. Patients with diabetic kidney disease have a worse prognosis in terms of mortality and morbidity, compared with patients who have diabetes alone. Strict control of blood pressure and blood glucose is the primary method for prevention of initial kidney damage and delaying further progression of existing damage. Other management approaches include the use of exogenous drugs that can effectively protect the kidneys from diabetes, such as sodium-glucose transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and renin-angiotensin-aldosterone system blockers. These drugs may protect against kidney injury through various molecular mechanisms. This review focuses on renal impairment in patients with type 2 diabetes; it discusses the direct and indirect effects of sodium-glucose transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and renin-angiotensin-aldosterone system blockers on diabetic kidney disease. Finally, it discusses the effects of combination treatment with two or three types of drugs in patients with chronic kidney disease.
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Affiliation(s)
- Zengguang Kuang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Ningning Hou
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, Weifang, China
| | - Chengxia Kan
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China
- Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Fang Han
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Hongyan Qiu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China.
- Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, Weifang, China.
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China.
| | - Xiaodong Sun
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, 2428 Yuhe Road, Weifang, 261031, Shandong, China.
- Branch of Shandong Provincial Clinical Research Center for Diabetes and Metabolic Diseases, Weifang, China.
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China.
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Karetnikova VN, Kchorlampenko AA, Kochergina AM, Osokina AV, Gruzdeva OV, Golubovskaia DP, Barbarash OL. Cardiometabolic Effects of Empagliflozin in Patients Undergoing Elective Percu-taneous Coronary Intervention for Type 2 Diabetes Mellitus. KARDIOLOGIIA 2022; 62:64-72. [PMID: 36636978 DOI: 10.18087/cardio.2022.12.n1838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 02/04/2022] [Indexed: 01/14/2023]
Abstract
Aim To evaluate cardiometabolic effects of empagliflozin in patients with ischemic heart disease and type 2 diabetes mellitus (DM) following elective percutaneous coronary intervention (PCI).Materials and methods Patients meeting the inclusion/non-inclusion criteria were randomized into two groups of equal number using simple randomization with successively assigned numbers. Group 1 included 37 patients (18 men and 19 women) who gave their consent for the treatment with empagliflozin 10 mg/day in addition to their previous hypoglycemic therapy. The drug administration started one month prior to the elective PCI and continued for the next 11 months (treatment duration, 12 months). Group 2 (comparison group) consisted of age- and DM duration-matched patients (37 patients; 18 men and 19 women) who continued on their hypoglycemic therapy previously prescribed by endocrinologists during the entire study period. Before the study, 36.11 % patients of the empagliflozin group and 27.03 % of the comparison group had unsatisfactory glycemic control as shown by the level of glycated hemoglobin (HbA1c).Results At 6 and 12 months of the study, fasting glycemia and HbA1c were significantly lower in the empagliflozin treatment group. The groups were comparable by the incidence of adverse outcomes: 8 (22.24 %) patients in the empagliflozin group and 10 (27.04 %) patients in the comparison group (р=0.787). The 12-month empagliflozin treatment reduced total cholesterol (C) by 5.56 % (p<0.05), low density lipoprotein (LDL) C by 3.67 % (p<0.05), visceral adipose tissue area (VATA) by 5.83 % (p<0.05), and subcutaneous adipose tissue area (SATA) by 3.54 % (p<0.05).Conclusion The empagliflozin treatment for 30 days prior to and after elective PCI can enhance the effectiveness of myocardial revascularization due to the demonstrated beneficial cardiometabolic effects.
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Affiliation(s)
- V N Karetnikova
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo; Kemerovo State Medical University, Kemerovo
| | - A A Kchorlampenko
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo
| | - A M Kochergina
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo; Kemerovo State Medical University, Kemerovo
| | - A V Osokina
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo
| | - O V Gruzdeva
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo; Kemerovo State Medical University, Kemerovo
| | | | - O L Barbarash
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo; Kemerovo State Medical University, Kemerovo
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Oura K, Morishita A, Tani J, Masaki T. Antitumor Effects and Mechanisms of Metabolic Syndrome Medications on Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:1279-1298. [PMID: 36545268 PMCID: PMC9760577 DOI: 10.2147/jhc.s392051] [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: 10/03/2022] [Accepted: 12/04/2022] [Indexed: 12/15/2022] Open
Abstract
Liver cancer has a high incidence and mortality rate worldwide, with hepatocellular carcinoma (HCC) being the most common histological type. With the decrease in the number of newly infected patients and the spread of antiviral therapy, hepatitis virus-negative chronic liver diseases including steatohepatitis are increasingly accounting for a large proportion of HCC, and an important clinical characteristic is the high prevalence of metabolic syndrome including hypertension, type 2 diabetes (T2D), dyslipidemia, and obesity. Since patients with steatohepatitis are less likely to undergo surveillance for early detection of HCC, they may be diagnosed at an advanced stage and have worse prognosis. Therefore, treatment strategies for patients with HCC caused by steatohepatitis, especially in advanced stages, become increasingly important. Further, hypertension, T2D, and dyslipidemia may occur as side effects during systemic treatment, and there will be increasing opportunities to prescribe metabolic syndrome medications, not only for originally comorbid diseases, but also for adverse events during HCC treatment. Interestingly, epidemiological studies have shown that patients taking some metabolic syndrome medications are less likely to develop various types of cancers, including HCC. Basic studies have also shown that these drugs have direct antitumor effects on HCC. In particular, angiotensin II receptor blockers (a drug group for treating hypertension), biguanides (a drug group for treating T2D), and statins (a drug group for treating dyslipidemia) have shown to elucidate antitumor effects against HCC. In this review, we focus on the antitumor effects of metabolic syndrome medications on HCC and their mechanisms based on recent literature. New therapeutic agents are also increasingly being reported. Analysis of the antitumor effects of metabolic syndrome medications on HCC and their mechanisms will be doubly beneficial for HCC patients with metabolic syndrome, and the use of these medications may be a potential strategy against HCC.
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Affiliation(s)
- Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan,Correspondence: Kyoko Oura, Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki, Kida, Kagawa, Japan, Tel +81-87-891-2156, Fax +81-87-891-2158, Email
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
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Sarohi V, Srivastava S, Basak T. A Comprehensive Outlook on Dilated Cardiomyopathy (DCM): State-Of-The-Art Developments with Special Emphasis on OMICS-Based Approaches. J Cardiovasc Dev Dis 2022; 9:jcdd9060174. [PMID: 35735803 PMCID: PMC9225617 DOI: 10.3390/jcdd9060174] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 05/12/2022] [Accepted: 05/19/2022] [Indexed: 02/04/2023] Open
Abstract
Dilated cardiomyopathy (DCM) remains an enigmatic cardiovascular disease (CVD) condition characterized by contractile dysfunction of the myocardium due to dilation of the ventricles. DCM is one of the major forms of CVD contributing to heart failure. Dilation of the left or both ventricles with systolic dysfunction, not explained by known causes, is a hallmark of DCM. Progression of DCM leads to heart failure. Genetic and various other factors greatly contribute to the development of DCM, but the etiology has still remained elusive in a large number of cases. A significant number of studies have been carried out to identify the genetic causes of DCM. These candidate-gene studies revealed that mutations in the genes of the fibrous, cytoskeletal, and sarcomeric proteins of cardiomyocytes result in the development of DCM. However, a significant proportion of DCM patients are idiopathic in nature. In this review, we holistically described the symptoms, causes (in adults and newborns), genetic basis, and mechanistic progression of DCM. Further, we also summarized the state-of-the-art diagnosis, available biomarkers, treatments, and ongoing clinical trials of potential drug regimens. DCM-mediated heart failure is on the rise worldwide including in India. The discovery of biomarkers with a better prognostic value is the need of the hour for better management of DCM-mediated heart failure patients. With the advent of next-generation omics-based technologies, it is now possible to probe systems-level alterations in DCM patients pertaining to the identification of novel proteomic and lipidomic biomarkers. Here, we also highlight the onset of a systems-level study in Indian DCM patients by applying state-of-the-art mass-spectrometry-based “clinical proteomics” and “clinical lipidomics”.
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Affiliation(s)
- Vivek Sarohi
- Indian Institute of Technology (IIT)-Mandi, School of Basic Sciences (SBS), Mandi 175075, HP, India; (V.S.); (S.S.)
- BioX Centre, Indian Institute of Technology (IIT)-Mandi, Mandi 175075, HP, India
| | - Shriya Srivastava
- Indian Institute of Technology (IIT)-Mandi, School of Basic Sciences (SBS), Mandi 175075, HP, India; (V.S.); (S.S.)
| | - Trayambak Basak
- Indian Institute of Technology (IIT)-Mandi, School of Basic Sciences (SBS), Mandi 175075, HP, India; (V.S.); (S.S.)
- BioX Centre, Indian Institute of Technology (IIT)-Mandi, Mandi 175075, HP, India
- Correspondence: ; Tel.: +91-1905-267826
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21
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Park JW, Kim JM, Noh JH, Kim KA, Chung H, Kim E, Kang M, Park JY. Pharmacokinetics of a Fixed-Dose Combination Product of Dapagliflozin and Linagliptin and Its Comparison with Co-Administration of Individual Tablets in Healthy Humans. Pharmaceutics 2022; 14:pharmaceutics14030591. [PMID: 35335967 PMCID: PMC8952231 DOI: 10.3390/pharmaceutics14030591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/24/2022] [Accepted: 03/03/2022] [Indexed: 02/04/2023] Open
Abstract
Dapagliflozin, a selective sodium–glucose co-transporter-2 inhibitor, and linagliptin, a competitive, reversible dipeptidyl peptidase-4 inhibitor, are commonly prescribed antidiabetic medications in general clinics. Since there are several merits to combining them in a fixed-dose combination product, this study investigated the pharmacokinetic equivalence between the individual component (IC) and fixed-combination drug product (FCDP) forms of dapagliflozin and linagliptin. A randomized, open-label, single-dose crossover study was conducted. All participants (n = 48) were randomly allocated to group A (period 1: ICs, period 2: FCDP) or group B (period 1: FCDP, period 2: ICs), and each group received either a single dose of IN-C009 (FCDP) or single doses of both dapagliflozin and linagliptin. There was no statistically significant difference found between the pharmacokinetic variables of FCDP and IC. The values of estimated geometric mean ratios and the 90% confidence interval for both maximum concentration and area under the plasma drug concentration–time curve were within the range of 0.8–1.25 for both dapagliflozin and linagliptin. The results of the clinical study demonstrated comparable pharmacokinetic characteristics between IC and FCDP forms of dapagliflozin and linagliptin. The combined use of dapagliflozin and linagliptin was safe and tolerable in both formulations.
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Affiliation(s)
- Jin-Woo Park
- Department of Clinical Pharmacology and Toxicology, Korea University College of Medicine, Korea University Anam Hospital, Seoul 02841, Korea; (J.-W.P.); (J.-M.K.); (J.H.N.); (K.-A.K.)
- Department of Neurology, Korea University Medical Center, Seoul 02841, Korea
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Jong-Min Kim
- Department of Clinical Pharmacology and Toxicology, Korea University College of Medicine, Korea University Anam Hospital, Seoul 02841, Korea; (J.-W.P.); (J.-M.K.); (J.H.N.); (K.-A.K.)
| | - Ji Hyeon Noh
- Department of Clinical Pharmacology and Toxicology, Korea University College of Medicine, Korea University Anam Hospital, Seoul 02841, Korea; (J.-W.P.); (J.-M.K.); (J.H.N.); (K.-A.K.)
| | - Kyoung-Ah Kim
- Department of Clinical Pharmacology and Toxicology, Korea University College of Medicine, Korea University Anam Hospital, Seoul 02841, Korea; (J.-W.P.); (J.-M.K.); (J.H.N.); (K.-A.K.)
| | - Hyewon Chung
- Department of Clinical Pharmacology and Toxicology, Korea University Guro Hospital, Seoul 08308, Korea;
| | - EunJi Kim
- HK Inno.N, Corporation, Seoul 04551, Korea; (E.K.); (M.K.)
| | - Minja Kang
- HK Inno.N, Corporation, Seoul 04551, Korea; (E.K.); (M.K.)
| | - Ji-Young Park
- Department of Clinical Pharmacology and Toxicology, Korea University College of Medicine, Korea University Anam Hospital, Seoul 02841, Korea; (J.-W.P.); (J.-M.K.); (J.H.N.); (K.-A.K.)
- Correspondence: ; Tel.: +82-02-920-6288
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22
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Song Y, Guo F, Liu Y, Huang F, Fan X, Zhao L, Qin G. Identification of circular RNAs and functional competing endogenous RNA networks in human proximal tubular epithelial cells treated with sodium-glucose cotransporter 2 inhibitor dapagliflozin in diabetic kidney disease. Bioengineered 2022; 13:3911-3929. [PMID: 35129424 PMCID: PMC8973950 DOI: 10.1080/21655979.2022.2031391] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Diabetic kidney disease (DKD) is a serious diabetes complication. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are novel anti-diabetes drugs that confer clinical renal protection. However, the molecular mechanisms involved remain unclear. Here, human proximal tubular epithelial cells (PTECs) were treated with normal glucose, high glucose, and anti-diabetes agents, including SGLT2i (dapagliflozin), metformin, and dipeptidyl peptidase-4 inhibitor (DPP-4i, vildagliptin) and microarray analysis was performed. Firstly, a total of 2,710 differentially expressed circular RNAs (circRNAs) were identified. Secondly, network pharmacology and transcriptomics analyses showed that the effects of dapagliflozin on PTECs primarily involved lipid metabolism, Rap1, and MAPK signaling pathways. Metformin mainly affected the AMPK and FOXO signaling pathways, whereas vildagliptin affected insulin secretion and the HIF-1 signaling pathway. Furthermore, circRNA-miRNA-mRNA networks, real-time reverse transcription-polymerase chain reaction (RT-PCR), and fluorescence in situ hybridization (FISH) assay revealed that the expression of hsa_circRNA_012448 was increased in PTECs treated with high glucose, whereas its expression was reversed by dapagliflozin. Finally, the hsa_circRNA_012448-hsa-miR-29b-2-5p-GSK3β pathway, involved in the oxidative stress response, was identified as an important pathway mediating the action of dapagliflozin against DKD. Overall, our study provides novel insights into the molecular mechanisms underlying the effects of dapagliflozin on DKD.
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Affiliation(s)
- Yi Song
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Feng Guo
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yifan Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Fengjuan Huang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xunjie Fan
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Lin Zhao
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guijun Qin
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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23
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Evaluating the effects of sodium glucose co-transporter -2 inhibitors from a renin-angiotensin-aldosterone system perspective in patients infected with COVID-19: contextualizing findings from the dapagliflozin in respiratory failure in patients with COVID-19 study. Mol Biol Rep 2022; 49:2321-2324. [PMID: 35102475 PMCID: PMC8803405 DOI: 10.1007/s11033-022-07183-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 01/20/2022] [Indexed: 12/18/2022]
Abstract
Numerous studies demonstrate parallels between CVD, type 2 diabetes mellitus (T2DM) and COVID-19 pathology, which accentuate pre-existing complications in patients infected with COVID-19 and potentially exacerbate the infection course. Antidiabetic drugs such as sodium-glucose transporter-2 (SGLT-2) inhibitors have garnered substantial attention recently due to their efficacy in reducing the severity of cardiorenal disease. The effect of SGLT-2 inhibitors in patients with COVID-19 remains unclear particularly since SGLT-2 inhibitors contribute to altering the RAAS cascade activity, which includes ACE-2, the major cell entry receptor for SARS-CoV2. A study, DARE-19, was carried out to unveil the effects of SGLT-2 inhibitor treatment on comorbid disease complications and concomitant COVID-19 outcomes and demonstrated no statistical significance. However, the need for further studies is essential to provide conclusive clinical findings.
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24
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Mascolo A, di Mauro G, Cappetta D, De Angelis A, Torella D, Urbanek K, Berrino L, Nicoletti GF, Capuano A, Rossi F. Current and future therapeutic perspective in chronic heart failure. Pharmacol Res 2021; 175:106035. [PMID: 34915125 DOI: 10.1016/j.phrs.2021.106035] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/29/2021] [Accepted: 12/10/2021] [Indexed: 12/11/2022]
Abstract
The incidence of heart failure is primarily flat or declining for a presumably reflecting better management of cardiovascular diseases, but that of heart failure with preserved ejection fraction (HFpEF) is probably increasing for the lack of an established effective treatment. Moreover, there is no specific pharmacological treatment for patients with heart failure with mildly reduced ejection fraction (HFmrEF) since no substantial prospective randomized clinical trial has been performed exclusively in such population. According to the recent 2021 European Society of Cardiology (ESC) guidelines, the triad composed of an Angiotensin Converting Enzyme inhibitor or Angiotensin Receptor-Neprilysin Inhibitor (ARNI), a beta-blocker, and a Mineralcorticoid Receptor Antagonist is the cornerstone therapy for all patients with heart failure with reduced ejection fraction (HFrEF) but a substantial gap exists for patients with HFpEF/HFmrEF. Despite the important role of the Renin-Angiotensin-Aldosterone System (RAAS) in heart failure pathophysiology, RAAS blockers were found ineffective for HFpEF patients. Indeed, even the new drug class of ARNI was found effective only in HFrEF patients. In this regard, a therapeutic alternative may be represented by drug stimulating the non-classic RAAS (ACE2 and A1-7) as well as other emerging drug classes (such as SGLT2 inhibitors). Reflecting on this global health burden and the gap in treatments among heart failure phenotypes, we summarize the leading players of heart failure pathophysiology, the available pharmacological treatments for each heart failure phenotype, and that in future development.
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Affiliation(s)
- Annamaria Mascolo
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Via Costantinopoli 16, 80138 Naples, Italy; Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy.
| | - Gabriella di Mauro
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Via Costantinopoli 16, 80138 Naples, Italy; Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - Donato Cappetta
- Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - Antonella De Angelis
- Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - Daniele Torella
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Konrad Urbanek
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Liberato Berrino
- Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - Giovanni Francesco Nicoletti
- Plastic Surgery Unit, University of Campania "Luigi Vanvitelli, Multidisciplinary Department of Medical Surgical and Dental Sciences, Napoli, Italy
| | - Annalisa Capuano
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Via Costantinopoli 16, 80138 Naples, Italy; Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - Francesco Rossi
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Via Costantinopoli 16, 80138 Naples, Italy; Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
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25
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Ravindran S, Munusamy S. Renoprotective mechanisms of sodium-glucose co-transporter 2 (SGLT2) inhibitors against the progression of diabetic kidney disease. J Cell Physiol 2021; 237:1182-1205. [PMID: 34713897 DOI: 10.1002/jcp.30621] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 10/02/2021] [Accepted: 10/08/2021] [Indexed: 12/19/2022]
Abstract
Sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) have emerged as a promising class of antidiabetic drugs with cardioprotective and renoprotective effects in patients with type 2 diabetes (T2D). The sodium-glucose co-transporters 1 and 2 (SGLT 1 and SGLT2) located in the renal proximal tubules are responsible for glucose reabsorption from the glomerular filtrate back into the systemic circulation. Inhibition of SGLT2, which accounts for about 90% of the glucose reabsorption, leads to a significant reduction in blood glucose levels and a concomitant increase in the urinary excretion of glucose (glycosuria). Multiple mechanisms contribute to the nephroprotective effects of SGLT2-Is in T2D patients. These include: (1) Restoration of the tubuloglomerular feedback by increasing sodium delivery at macula densa, leading to afferent arteriolar constriction and reduced glomerular hyperfiltration, (2) Decreased activation of the intra-renal renin-angiotensin-aldosterone system, which also contributes to reducing glomerular hyperfiltration, (3) Increased production of ketone bodies, which serves as an alternate fuel for adenosine triphosphate production in mitochondria, which helps in attenuating inflammation, and (4) Protection against hypoxia, oxidative stress, and fibrosis. This review elaborates on the key mechanisms that underlie the nephroprotective effects and the adverse effects of SGLT2-Is in T2D patients with progressive diabetic kidney disease.
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Affiliation(s)
| | - Shankar Munusamy
- Department of Pharmaceutical and Administrative Sciences, Drake University College of Pharmacy and Health Sciences, Des Moines, Iowa, USA
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26
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Seidu S, Kunutsor SK, Topsever P, Khunti K. Benefits and harms of sodium-glucose co-transporter-2 inhibitors (SGLT2-I) and renin-angiotensin-aldosterone system inhibitors (RAAS-I) versus SGLT2-Is alone in patients with type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. ENDOCRINOLOGY DIABETES & METABOLISM 2021; 5:e00303. [PMID: 34636161 PMCID: PMC8754244 DOI: 10.1002/edm2.303] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/19/2021] [Accepted: 09/21/2021] [Indexed: 01/22/2023]
Abstract
Introduction It is uncertain if the combination of sodium‐glucose co‐transporter 2 inhibitors (SGLT2‐Is) and renin‐angiotensin‐aldosterone system inhibitors (RAAS‐Is) provides better cardio‐renal clinical outcomes in people with type 2 diabetes mellitus (T2DM) compared with SGLT2‐Is alone. Using a systematic review and meta‐analysis of randomized controlled trials (RCTs), we evaluated the efficacy and safety with respect to cardio‐renal outcomes of the combination of SGLT2 and RAAS inhibitors vs SGLT2‐Is in patients with T2DM. Methods Studies were identified from MEDLINE, Embase, the Cochrane Library and search of bibliographies to May 2021. The Cochrane risk of bias tool was used to assess the risk of bias of each study. Study‐specific risk ratios (RRs) with 95% confidence intervals (CIs) were pooled. Quality of the evidence was assessed using GRADE. Results Nine articles comprising 8 RCT evaluations (n = 34,551 participants) that compared SGLT2‐Is with placebo in patients with T2DM against a background of standard care and reported subgroup results for those treated with or without RAAS‐Is at baseline were included. No RCT specifically investigated the combination of SGLT2 and RAAS inhibitors compared with SGLT2‐Is alone. The RRs (95% CIs) for composite cardiovascular outcome and composite CVD death/heart failure hospitalization comparing SGLT2‐Is vs placebo in patients on RAAS‐Is were 0.93 (0.85–1.01) and 0.88 (0.76–1.02), respectively. The corresponding estimates for patients not on RAAS‐Is were 0.78 (0.65–0.93) and 0.73 (0.65–0.82), respectively. There was no evidence of interactions between RAAS‐I status and the effects of SGLT2‐Is for both outcomes. Single study results showed that SGLT2‐Is vs placebo reduced the risk of composite kidney outcome and cardiovascular death in patients with RAAS inhibition. The effect of SGLT2 inhibition vs placebo on kidney parameters, genital infections, volume depletion, hyperkalaemia, hypokalaemia, hypoglycaemia and other adverse events was similar in patients with or without RAAS inhibition. The quality of the evidence ranged from very low to moderate. Conclusions Aggregate published data suggest that the combination of SGLT2 and RAAS inhibitors in the treatment of patients with T2DM may be similar in efficacy and safety if not superior to SGLT2‐Is alone. Head‐to‐head comparisons of the two interventions are warranted to inform T2DM management. The use of SGLT2 inhibition as a first‐line therapy in T2DM or its early use in the prevention of renal deterioration and cardiovascular complications in addition to its glycaemic control deserves further study.
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Affiliation(s)
- Samuel Seidu
- Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK
| | - Setor K Kunutsor
- National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK.,Translational Health Sciences, Bristol Medical School, Learning & Research Building (Level 1), University of Bristol, Southmead Hospital, Bristol, UK
| | - Pinar Topsever
- Department of Family Medicine, Acibadem Mehmet Ali Aydinlar University School of Medicine, Kerem Aydinlar Campus, Atasehir, Turkey
| | - Kamlesh Khunti
- Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK
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27
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Wang J, Xiang H, Lu Y, Wu T, Ji G. New progress in drugs treatment of diabetic kidney disease. Biomed Pharmacother 2021; 141:111918. [PMID: 34328095 DOI: 10.1016/j.biopha.2021.111918] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/08/2021] [Accepted: 07/12/2021] [Indexed: 02/08/2023] Open
Abstract
Diabetic kidney disease (DKD) is not only one of the main complications of diabetes, but also the leading cause of the end-stage renal disease (ESRD). The occurrence and development of DKD have always been a serious clinical problem that leads to the increase of morbidity and mortality and the severe damage to the quality of life of human beings. Controlling blood glucose, blood pressure, blood lipids, and improving lifestyle can help slow the progress of DKD. In recent years, with the extensive research on the pathological mechanism and molecular mechanism of DKD, there are more and more new drugs based on this, such as new hypoglycemic drugs sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors with good efficacy in clinical treatment. Besides, there are some newly developed drugs, including protein kinase C (PKC) inhibitors, advanced glycation end product (AGE) inhibitors, aldosterone receptor inhibitors, endothelin receptor (ETR) inhibitors, transforming growth factor-β (TGF-β) inhibitors, Rho kinase (ROCK) inhibitors and so on, which show positive effects in animal or clinical trials and bring hope for the treatment of DKD. In this review, we sort out the progress in the treatment of DKD in recent years, the research status of some emerging drugs, and the potential drugs for the treatment of DKD in the future, hoping to provide some directions for clinical treatment of DKD.
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Affiliation(s)
- Junmin Wang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hongjiao Xiang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yifei Lu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Guang Ji
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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28
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Fang Q, Liu N, Zheng B, Guo F, Zeng X, Huang X, Ouyang D. Roles of Gut Microbial Metabolites in Diabetic Kidney Disease. Front Endocrinol (Lausanne) 2021; 12:636175. [PMID: 34093430 PMCID: PMC8173181 DOI: 10.3389/fendo.2021.636175] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes is a highly prevalent metabolic disease that has emerged as a global challenge due to its increasing prevalence and lack of sustainable treatment. Diabetic kidney disease (DKD), which is one of the most frequent and severe microvascular complications of diabetes, is difficult to treat with contemporary glucose-lowering medications. The gut microbiota plays an important role in human health and disease, and its metabolites have both beneficial and harmful effects on vital physiological processes. In this review, we summarize the current findings regarding the role of gut microbial metabolites in the development and progression of DKD, which will help us better understand the possible mechanisms of DKD and explore potential therapeutic approaches for DKD.
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Affiliation(s)
- Qing Fang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, China
| | - Na Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, China
| | - Binjie Zheng
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, China
| | - Fei Guo
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, China
| | - Xiangchang Zeng
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, China
| | - Xinyi Huang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, China
| | - Dongsheng Ouyang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Changsha, China
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, China
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29
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Wu CW, Chen HY, Yang CW, Chen YC. Deciphering the Efficacy and Mechanisms of Chinese Herbal Medicine for Diabetic Kidney Disease by Integrating Web-Based Biochemical Databases and Real-World Clinical Data: Retrospective Cohort Study. JMIR Med Inform 2021; 9:e27614. [PMID: 33973855 PMCID: PMC8150407 DOI: 10.2196/27614] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/01/2021] [Accepted: 04/11/2021] [Indexed: 12/14/2022] Open
Abstract
Background Diabetic kidney disease (DKD) is one of the most crucial causes of chronic kidney disease (CKD). However, the efficacy and biomedical mechanisms of Chinese herbal medicine (CHM) for DKD in clinical settings remain unclear. Objective This study aimed to analyze the outcomes of DKD patients with CHM-only management and the possible molecular pathways of CHM by integrating web-based biomedical databases and real-world clinical data. Methods A total of 152,357 patients with incident DKD from 2004 to 2012 were identified from the National Health Insurance Research Database (NHIRD) in Taiwan. The risk of mortality was estimated with the Kaplan-Meier method and Cox regression considering demographic covariates. The inverse probability of treatment weighting was used for confounding bias between CHM users and nonusers. Furthermore, to decipher the CHM used for DKD, we analyzed all CHM prescriptions using the Chinese Herbal Medicine Network (CMN), which combined association rule mining and social network analysis for all CHM prescriptions. Further, web-based biomedical databases, including STITCH, STRING, BindingDB, TCMSP, TCM@Taiwan, and DisGeNET, were integrated with the CMN and commonly used Western medicine (WM) to explore the differences in possible target proteins and molecular pathways between CHM and WM. An application programming interface was used to assess these online databases to obtain the latest biomedical information. Results About 13.7% (20,947/131,410) of patients were classified as CHM users among eligible DKD patients. The median follow-up duration of all patients was 2.49 years. The cumulative mortality rate in the CHM cohort was significantly lower than that in the WM cohort (28% vs 48%, P<.001). The risk of mortality was 0.41 in the CHM cohort with covariate adjustment (99% CI 0.38-0.43; P<.001). A total of 173,525 CHM prescriptions were used to construct the CMN with 11 CHM clusters. CHM covered more DKD-related proteins and pathways than WM; nevertheless, WM aimed at managing DKD more specifically. From the overrepresentation tests carried out by the online website Reactome, the molecular pathways covered by the CHM clusters in the CMN and WM seemed distinctive but complementary. Complementary effects were also found among DKD patients with concurrent WM and CHM use. The risk of mortality for CHM users under renin-angiotensin-aldosterone system (RAAS) inhibition therapy was lower than that for CHM nonusers among DKD patients with hypertension (adjusted hazard ratio [aHR] 0.47, 99% CI 0.45-0.51; P<.001), chronic heart failure (aHR 0.43, 99% CI 0.37-0.51; P<.001), and ischemic heart disease (aHR 0.46, 99% CI 0.41-0.51; P<.001). Conclusions CHM users among DKD patients seemed to have a lower risk of mortality, which may benefit from potentially synergistic renoprotection effects. The framework of integrating real-world clinical databases and web-based biomedical databases could help in exploring the roles of treatments for diseases.
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Affiliation(s)
- Chien-Wei Wu
- Division of Chinese Internal and Pediatric Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Hsing-Yu Chen
- Division of Chinese Internal and Pediatric Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ching-Wei Yang
- Division of Chinese Internal and Pediatric Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Chun Chen
- School of Medicine, Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Institute of Hospital and Health Care Administration, National Yang Ming Chiao Tung University, Taipei, Taiwan
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Chen L, Wu J, Hu B, Liu C, Wang H. The Role of Cell Division Autoantigen 1 (CDA1) in Renal Fibrosis of Diabetic Nephropathy. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6651075. [PMID: 33997036 PMCID: PMC8102118 DOI: 10.1155/2021/6651075] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 04/05/2021] [Accepted: 04/16/2021] [Indexed: 01/10/2023]
Abstract
The common kidney disease diabetic nephropathy (DN) accounts for significant morbidity and mortality in patients with diabetes, and its effective diagnosis in incipient stages is still lacking. Renal fibrosis is the main pathological feature of DN. Cell division autoantigen 1 (CDA1), a phosphorylated protein encoded by TSPYL2 on the X chromosome, plays a fibrogenic role by modulating the transforming growth factor-β (TGF-β) signaling, but the exact mechanism remains unclear. TGF-β signaling has been recognized as the key factor in promoting the development and progression of DN. At present, strict control of blood sugar and blood pressure can significantly lower the development and progression of DN in the early stages, and many studies have shown that blocking TGF-β signaling can delay the progress of DN. However, TGF-β is a multifunctional cytokine. Its direct intervention may result in increased side effects. Therefore, the targeted intervention of CDA1 not only can block the TGF-β signaling pathway but also can reduce these side effects. In this article, we review the main physiological roles of CDA1, with particular attention to its effect and potential mechanism in the renal fibrosis of DN.
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Affiliation(s)
- LinLin Chen
- Affiliated Ren He Hospital of China Three Gorges University, Yichang 443002, China
- Medical School, China Three Gorges University, 8 Daxue Road, Yichang 443002, China
| | - Jiao Wu
- Affiliated Ren He Hospital of China Three Gorges University, Yichang 443002, China
| | - Bin Hu
- Affiliated Ren He Hospital of China Three Gorges University, Yichang 443002, China
| | - Changbai Liu
- Medical School, China Three Gorges University, 8 Daxue Road, Yichang 443002, China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, 8 Daxue Road, Yichang 443002, China
| | - Hu Wang
- Medical School, China Three Gorges University, 8 Daxue Road, Yichang 443002, China
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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Lo CWH, Fei Y, Cheung BMY. Cardiovascular Outcomes in Trials of New Antidiabetic Drug Classes. Card Fail Rev 2021; 7:e04. [PMID: 33747548 PMCID: PMC7970669 DOI: 10.15420/cfr.2020.19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [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: 11/11/2020] [Indexed: 12/28/2022] Open
Abstract
Type 2 diabetes is among the most prevalent chronic diseases worldwide and the prevention of associated cardiovascular complications is an important treatment goal. Sodium–glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are second-line options after metformin, while cardiovascular outcome trials have been conducted to establish the cardiovascular safety of these antidiabetic drug classes. SGLT2 inhibitors have been shown to have the best overall mortality, renal and cardiovascular outcomes. Reduction in hospitalisation for heart failure is particularly consistent. GLP-1 receptor agonists have also showed some benefits, especially in stroke prevention. DPP-4 inhibitors showed neutral effects on cardiovascular outcomes, but may increase the incidence of heart failure. Favourable outcomes observed in trials of SGLT2 inhibitors mean that these should be the preferred second-line option. DPP-4 inhibitors are useful for patients with diabetes at low cardiovascular risk.
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Affiliation(s)
- Chris Wai Hang Lo
- Division of Clinical Pharmacology and Therapeutics, Department of Medicine, The University of Hong Kong Pokfulam, Hong Kong, China
| | - Yue Fei
- Division of Clinical Pharmacology and Therapeutics, Department of Medicine, The University of Hong Kong Pokfulam, Hong Kong, China
| | - Bernard Man Yung Cheung
- Division of Clinical Pharmacology and Therapeutics, Department of Medicine, The University of Hong Kong Pokfulam, Hong Kong, China.,State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong Pokfulam, Hong Kong, China.,Institute of Cardiovascular Science and Medicine, The University of Hong Kong Pokfulam, Hong Kong, China
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Lu HC, Dai WN, He LY. Epigenetic Histone Modifications in the Pathogenesis of Diabetic Kidney Disease. Diabetes Metab Syndr Obes 2021; 14:329-344. [PMID: 33519221 PMCID: PMC7837569 DOI: 10.2147/dmso.s288500] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022] Open
Abstract
Diabetic kidney disease (DKD), as the main complication of diabetes mellitus, is the primary cause of the end-stage renal disease (ESRD) and the most common chronic kidney disease. Overall, 30-40% of patients with type 1 and type 2 diabetes eventually develop DKD. Although some diabetes patients have intensified glycemic control, they still develop diabetic kidney disease. Current treatment methods can alleviate but do not markedly halt disease development, resulting in renal failure and severe complications, even contributing to elevated morbidity and mortality rates. DKD is a disease with interactions of genes and the environment. Emerging evidence indicates that DKD-associated key genes are also regulated by the epigenetic mechanism. Recently, increasing researches involving cells and experimental animals demonstrated that histone post-translational modifications can mediate gene expression, which correlated with diabetic kidney disease. Novel therapeutic strategies for epigenetic events could be beneficial for the early detection and treatment of DKD to prevent it from developing into end-stage renal disease (ESRD). In this review, we discuss prior findings in the field of histone modifications in DKD, especially histone acetylation and histone methylation. We then focus on recent developments in histone acetylation and methylation involved in the pathogenesis of DKD.
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Affiliation(s)
- Heng-Cheng Lu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, People’s Republic of China
| | - Wen-Ni Dai
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, People’s Republic of China
| | - Li-Yu He
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, People’s Republic of China
- Correspondence: Li-Yu He Department of Nephrology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, 139 Renmin Road, Changsha, Hunan, People’s Republic of ChinaTel +8673185292064Fax +8673185295843 Email
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Khorlampenko AA, Karetnikova VN, Kochergina AM, Ignatova JS, Dyleva JA, Gruzdeva OV, Barbarash OL. [Effect of empagliflosin on renal filtration in patients with coronary heart disease undergoing percutaneous coronary intervention]. ACTA ACUST UNITED AC 2020; 60:825. [PMID: 32720618 DOI: 10.18087/cardio.2020.6.n825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 04/14/2020] [Accepted: 04/19/2020] [Indexed: 11/18/2022]
Abstract
Aim To evaluate the effect of empagliflozin on glycemia and renal filtration function in patients with stable ischemic heart disease (IHD) and type 2 diabetes mellitus (DM2) who underwent a percutaneous coronary intervention (PCI).Materials and methods This study included 40 patients with stable IHD and DM2 (age, 63 (58; 65) years; DM2 duration, 7 (4; 15) years) who had indications for an elective PCI. At baseline in the total sample, the level of glycated hemoglobin was 7.2 (6.5; 8.3)%; 48.7 % failed to achieve glycemic goals. A decrease in glomerular filtration rate (GFR) to below 60 ml/min/1.73 m2 was observed in 10.3 % of patients. All patients were divided into two group by simple randomization with successively assigned numbers. The main group consisted of 20 patients who received empagliflozin 10 mg/day in addition to their previous hypoglycemic therapy irrespective of their baseline glycemic control. Patients of the comparison group (n=20) continued on their previous hypoglycemic therapy as prescribed by their endocrinologist. The follow-up duration was 6 months. Statistical analysis was performed with the Statistica 10.0 software.Results The empagliflozin treatment improved the glycemic control; in the comparison group, no significant changes in glycemic control were observed. In both groups, GFR significantly decreased during the follow-up period; median decreases in GFR were -6.0 (-16.0; 4.0) and -8.4 (-26.5; 2.5) ml/min / 1.73 m2 in the main and comparison groups, respectively (p = 0.646). No significant changes in 24-h proteinuria were observed for patients taking empagliflozin. In the control group, the 24-h urinary protein excretion significantly progressed (p=0.011) during the follow-up period.Conclusion In patients with DM2 and stable IHD who underwent a PCI, addition of empagliflozin 10 mg/day to their current hypoglycemic therapy was associated with a significant improvement of glycemic control. The decrease in GFR during the empagliflozin treatment did not significantly differ from the value for patient receiving the other hypoglycemic therapy.
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Affiliation(s)
- A A Khorlampenko
- Federal State Budgetary Institution of Higher Professional Education Kemerovo State Medical University of the Ministry of Healthcare of the Russian Federation, Kemerovo, Russia
| | - V N Karetnikova
- Federal State Budgetary Institution of Higher Professional Education Kemerovo State Medical University of the Ministry of Healthcare of the Russian Federation, Kemerovo, Russia
| | - A M Kochergina
- Federal State Budgetary Institution of Higher Professional Education Kemerovo State Medical University of the Ministry of Healthcare of the Russian Federation, Kemerovo, Russia
| | - J S Ignatova
- Federal State Budgetary Institution of Higher Professional Education Kemerovo State Medical University of the Ministry of Healthcare of the Russian Federation, Kemerovo, Russia
| | - J A Dyleva
- Federal State Budgetary Institution Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
| | - O V Gruzdeva
- Federal State Budgetary Institution Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
| | - O L Barbarash
- Federal State Budgetary Institution Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
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Srivastava SP, Goodwin JE. Cancer Biology and Prevention in Diabetes. Cells 2020; 9:cells9061380. [PMID: 32498358 PMCID: PMC7349292 DOI: 10.3390/cells9061380] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/25/2020] [Accepted: 05/30/2020] [Indexed: 02/07/2023] Open
Abstract
The available evidence suggests a complex relationship between diabetes and cancer. Epidemiological data suggest a positive correlation, however, in certain types of cancer, a more complex picture emerges, such as in some site-specific cancers being specific to type I diabetes but not to type II diabetes. Reports share common and differential mechanisms which affect the relationship between diabetes and cancer. We discuss the use of antidiabetic drugs in a wide range of cancer therapy and cancer therapeutics in the development of hyperglycemia, especially antineoplastic drugs which often induce hyperglycemia by targeting insulin/IGF-1 signaling. Similarly, dipeptidyl peptidase 4 (DPP-4), a well-known target in type II diabetes mellitus, has differential effects on cancer types. Past studies suggest a protective role of DPP-4 inhibitors, but recent studies show that DPP-4 inhibition induces cancer metastasis. Moreover, molecular pathological mechanisms of cancer in diabetes are currently largely unclear. The cancer-causing mechanisms in diabetes have been shown to be complex, including excessive ROS-formation, destruction of essential biomolecules, chronic inflammation, and impaired healing phenomena, collectively leading to carcinogenesis in diabetic conditions. Diabetes-associated epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndMT) contribute to cancer-associated fibroblast (CAF) formation in tumors, allowing the epithelium and endothelium to enable tumor cell extravasation. In this review, we discuss the risk of cancer associated with anti-diabetic therapies, including DPP-4 inhibitors and SGLT2 inhibitors, and the role of catechol-o-methyltransferase (COMT), AMPK, and cell-specific glucocorticoid receptors in cancer biology. We explore possible mechanistic links between diabetes and cancer biology and discuss new therapeutic approaches.
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Affiliation(s)
- Swayam Prakash Srivastava
- Department of Pediatrics, Yale University School of Medicine, Yale University, New Haven, CT 06520-8064, USA
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520-8066, USA
- Correspondence: (S.P.S.); (J.E.G.)
| | - Julie E. Goodwin
- Department of Pediatrics, Yale University School of Medicine, Yale University, New Haven, CT 06520-8064, USA
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520-8066, USA
- Correspondence: (S.P.S.); (J.E.G.)
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Kruger D, Valentine V. Canagliflozin for the Treatment of Diabetic Kidney Disease and Implications for Clinical Practice: A Narrative Review. Diabetes Ther 2020; 11:1237-1250. [PMID: 32405876 PMCID: PMC7261301 DOI: 10.1007/s13300-020-00826-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Indexed: 12/17/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) affects millions of people worldwide, elevating their risk of developing a range of complications, including chronic kidney disease (CKD). People with T2DM and CKD (i.e., diabetic kidney disease, DKD) have an increased risk of progressing to end-stage kidney disease (ESKD), experiencing cardiovascular complications, and premature death. Despite this, DKD is primarily addressed through management of risk factors, and there are few pharmaceutical treatments capable of reversing or delaying disease progression. Canagliflozin is a sodium glucose co-transporter 2 inhibitor that was initially developed as a blood glucose-lowering agent for people with T2DM. Evidence from clinical trials of canagliflozin in people with T2DM, as well as evidence from cardiovascular outcomes trials in people with T2DM and high cardiovascular risk, provided preliminary evidence suggesting that it may also have beneficial renal effects. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was a dedicated renal outcomes trial of canagliflozin that assessed its renal effects in people with DKD. Overall, the CREDENCE trial demonstrated that canagliflozin improves renal outcomes and slows early disease progression in people with DKD. These data supported the approval of canagliflozin for the treatment DKD, the first new treatment in almost 20 years; therefore, it is important for clinicians to understand how to implement this treatment in their clinical practice.
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Korbut AI, Taskaeva IS, Bgatova NP, Muraleva NA, Orlov NB, Dashkin MV, Khotskina AS, Zavyalov EL, Konenkov VI, Klein T, Klimontov VV. SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes. Int J Mol Sci 2020; 21:2987. [PMID: 32340263 PMCID: PMC7215949 DOI: 10.3390/ijms21082987] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 04/19/2020] [Accepted: 04/21/2020] [Indexed: 02/08/2023] Open
Abstract
Recent data have indicated the emerging role of glomerular autophagy in diabetic kidney disease. We aimed to assess the effect of the SGLT2 inhibitor empagliflozin, the DPP4 inhibitor linagliptin, and their combination, on glomerular autophagy in a model of type 2 diabetes. Eight-week-old male db/db mice were randomly assigned to treatment with empagliflozin, linagliptin, empagliflozin-linagliptin or vehicle for 8 weeks. Age-matched non-diabetic db/+ mice acted as controls. To estimate glomerular autophagy, immunohistochemistry for beclin-1 and LAMP-1 was performed. Podocyte autophagy was assessed by counting the volume density (Vv) of autophagosomes, lysosomes and autolysosomes by transmission electron microscopy. LC3B and LAMP-1, autophagy markers, and caspase-3 and Bcl-2, apoptotic markers, were evaluated in renal cortex by western blot. Vehicle-treated db/db mice had weak glomerular staining for beclin-1 and LAMP-1 and reduced Vv of autophagosomes, autolysosomes and lysosomes in podocytes. Empagliflozin and linagliptin, both as monotherapy and in combination, enhanced the areas of glomerular staining for beclin-1 and LAMP-1 and increased Vv of autophagosomes and autolysosomes in podocytes. Renal LC3B and Bcl-2 were restored in actively treated animals. LAMP-1 expression was enhanced in the empagliflozin group; caspase-3 expression decreased in the empagliflozin-linagliptin group only. Mesangial expansion, podocyte foot process effacement and urinary albumin excretion were mitigated by both agents. The data provide further explanation for the mechanism of the renoprotective effect of SGLT2 inhibitors and DPP4 inhibitors in diabetes.
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Affiliation(s)
- Anton I. Korbut
- Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), Timakov Str. 2, 630060 Novosibirsk, Russia
| | - Iuliia S. Taskaeva
- Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), Timakov Str. 2, 630060 Novosibirsk, Russia
| | - Nataliya P. Bgatova
- Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), Timakov Str. 2, 630060 Novosibirsk, Russia
| | - Natalia A. Muraleva
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia
| | - Nikolai B. Orlov
- Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), Timakov Str. 2, 630060 Novosibirsk, Russia
| | - Maksim V. Dashkin
- Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), Timakov Str. 2, 630060 Novosibirsk, Russia
| | - Anna S. Khotskina
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia
| | - Evgenii L. Zavyalov
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia
| | - Vladimir I. Konenkov
- Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), Timakov Str. 2, 630060 Novosibirsk, Russia
| | - Thomas Klein
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany
| | - Vadim V. Klimontov
- Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), Timakov Str. 2, 630060 Novosibirsk, Russia
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Choxi R, Roy S, Stamatouli A, Mayer SB, Jovin IS. Type 2 diabetes mellitus and cardiovascular disease: focus on the effect of antihyperglycemic treatments on cardiovascular outcomes. Expert Rev Cardiovasc Ther 2020; 18:187-199. [PMID: 32306789 DOI: 10.1080/14779072.2020.1756778] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Introduction: Type 2 diabetes mellitus and cardiovascular disease contribute to significant morbidity, mortality, and health-care resource expenditure. The pathophysiological and clinical associations between diabetes and cardiovascular disease have been the subject of multiple studies, most recently culminating in large trials of several new antiglycemic agents being found to confer additional cardiovascular risk reduction. Understanding the potential cardiovascular benefits of antiglycemic medications offers the unique opportunity to reduce the morbidity and mortality presented by both diseases at once.Areas covered: The literature search was comprised of a Pubmed search querying 'cardiovascular outcomes' and 'diabetes'. This article reviews the pathophysiology of cardiovascular complications in type 2 diabetes and the cardiovascular outcome trials related to newer antiglycemic medications.Expert opinion: The treatment of patients with type 2 diabetes mellitus and cardiovascular disease is rapidly advancing. In particular, the sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated cardiovascular benefit by reducing major adverse cardiovascular events and cardiovascular mortality. Future directions of the treatment of type 2 diabetes and cardiovascular disease will focus on targeting and preventing diabetic cardiomyopathy and further defining the role of SGLT2 inhibitors and of GLP-1 receptor agonists in additional patient populations.
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Affiliation(s)
- Ravi Choxi
- Department of Medicine, Virginia Commonwealth University Health System, USA.,Department of Medicine, Veterans Affairs Medical Center, Richmond, VA, USA
| | - Sumon Roy
- Department of Medicine, Virginia Commonwealth University Health System, USA.,Department of Medicine, Veterans Affairs Medical Center, Richmond, VA, USA
| | | | - Stéphanie B Mayer
- Department of Medicine, Virginia Commonwealth University Health System, USA.,Department of Medicine, Veterans Affairs Medical Center, Richmond, VA, USA
| | - Ion S Jovin
- Department of Medicine, Virginia Commonwealth University Health System, USA.,Department of Medicine, Veterans Affairs Medical Center, Richmond, VA, USA
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Barrera-Chimal J, Jaisser F. Pathophysiologic mechanisms in diabetic kidney disease: A focus on current and future therapeutic targets. Diabetes Obes Metab 2020; 22 Suppl 1:16-31. [PMID: 32267077 DOI: 10.1111/dom.13969] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/07/2020] [Accepted: 01/13/2020] [Indexed: 12/22/2022]
Abstract
Diabetic kidney disease (DKD) is the primary cause of chronic kidney disease around the globe and is one of the main complications in patients with type 1 and 2 diabetes. The standard treatment for DKD is drugs controlling hyperglycemia and high blood pressure. Renin angiotensin aldosterone system blockade and sodium glucose cotransporter 2 (SGLT2) inhibition have yielded promising results in DKD, but many diabetic patients on such treatments nevertheless continue to develop DKD, leading to kidney failure and cardiovascular comorbidities. New therapeutic options are urgently required. We review here the promising therapeutic avenues based on insights into the mechanisms of DKD that have recently emerged, including mineralocorticoid receptor antagonists, SGLT2 inhibitors, glucagon-like peptide-1 receptor agonist, endothelin receptor A inhibition, anti-inflammatory agents, autophagy activators and epigenetic remodelling. The involvement of several molecular mechanisms in DKD pathogenesis, together with the genetic and epigenetic variability of this condition, makes it difficult to target this heterogeneous patient population with a single drug. Personalized medicine, taking into account the genetic and mechanistic variability, may therefore improve renal and cardiovascular protection in diabetic patients with DKD.
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Affiliation(s)
- Jonatan Barrera-Chimal
- Laboratorio de Fisiología Cardiovascular y Trasplante Renal, Unidad de Investigación en Medicina Traslacional, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Frédéric Jaisser
- INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne University, Paris Descartes University, Paris, France
- INSERM U1116, Clinical Investigation Centre, Lorraine University, Vandoeuvre-lès-Nancy, France
- INI-CRCT (Cardiovascular and Renal Clinical Trialists) F-CRIN Network, Nancy, France
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Lavoz C, Rayego-Mateos S, Orejudo M, Opazo-Ríos L, Marchant V, Marquez-Exposito L, Tejera-Muñoz A, Navarro-González JF, Droguett A, Ortiz A, Egido J, Mezzano S, Rodrigues-Diez RR, Ruiz-Ortega M. Could IL-17A Be a Novel Therapeutic Target in Diabetic Nephropathy? J Clin Med 2020; 9:E272. [PMID: 31963845 PMCID: PMC7019373 DOI: 10.3390/jcm9010272] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/11/2020] [Accepted: 01/13/2020] [Indexed: 12/15/2022] Open
Abstract
Chronic kidney disease has become a major medical issue in recent years due to its high prevalence worldwide, its association with premature mortality, and its social and economic implications. A number of patients gradually progress to end-stage renal disease (ESRD), requiring then dialysis and kidney transplantation. Currently, approximately 40% of patients with diabetes develop kidney disease, making it the most prevalent cause of ESRD. Thus, more effective therapies for diabetic nephropathy are needed. In preclinical studies of diabetes, anti-inflammatory therapeutic strategies have been used to protect the kidneys. Recent evidence supports that immune cells play an active role in the pathogenesis of diabetic nephropathy. Th17 immune cells and their effector cytokine IL-17A have recently emerged as promising targets in several clinical conditions, including renal diseases. Here, we review current knowledge regarding the involvement of Th17/IL-17A in the genesis of diabetic renal injury, as well as the rationale behind targeting IL-17A as an additional therapy in patients with diabetic nephropathy.
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Affiliation(s)
- Carolina Lavoz
- Laboratorio de Nefrología, Facultad de Medicina, Universidad Austral de Chile, Valdivia 5090000, Chile; (C.L.); (V.M.); (A.D.); (S.M.)
| | - Sandra Rayego-Mateos
- Vascular and Renal Translational Research Group, Institut de Recerca Biomèdica de Lleida (IRBLleida), 25198 Lleida, Spain;
- Red de Investigación Renal (REDINREN), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.O.); (L.M.-E.); (A.T.-M.); (A.O.)
| | - Macarena Orejudo
- Red de Investigación Renal (REDINREN), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.O.); (L.M.-E.); (A.T.-M.); (A.O.)
- Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
| | - Lucas Opazo-Ríos
- Renal, Vascular and Diabetes Research Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain; (L.O.-R.); (J.E.)
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Vanessa Marchant
- Laboratorio de Nefrología, Facultad de Medicina, Universidad Austral de Chile, Valdivia 5090000, Chile; (C.L.); (V.M.); (A.D.); (S.M.)
- Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
| | - Laura Marquez-Exposito
- Red de Investigación Renal (REDINREN), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.O.); (L.M.-E.); (A.T.-M.); (A.O.)
- Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
| | - Antonio Tejera-Muñoz
- Red de Investigación Renal (REDINREN), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.O.); (L.M.-E.); (A.T.-M.); (A.O.)
- Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
| | - Juan F. Navarro-González
- Unidad de Investigación y Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain;
| | - Alejandra Droguett
- Laboratorio de Nefrología, Facultad de Medicina, Universidad Austral de Chile, Valdivia 5090000, Chile; (C.L.); (V.M.); (A.D.); (S.M.)
| | - Alberto Ortiz
- Red de Investigación Renal (REDINREN), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.O.); (L.M.-E.); (A.T.-M.); (A.O.)
- Nephrology and Hypertension, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
| | - Jesús Egido
- Renal, Vascular and Diabetes Research Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain; (L.O.-R.); (J.E.)
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Sergio Mezzano
- Laboratorio de Nefrología, Facultad de Medicina, Universidad Austral de Chile, Valdivia 5090000, Chile; (C.L.); (V.M.); (A.D.); (S.M.)
| | - Raúl R. Rodrigues-Diez
- Red de Investigación Renal (REDINREN), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.O.); (L.M.-E.); (A.T.-M.); (A.O.)
- Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
| | - Marta Ruiz-Ortega
- Red de Investigación Renal (REDINREN), Instituto de Salud Carlos III, 28029 Madrid, Spain; (M.O.); (L.M.-E.); (A.T.-M.); (A.O.)
- Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, Fundación Instituto de Investigación Sanitaria-Fundación Jiménez Díaz-Universidad Autónoma Madrid, 28040 Madrid, Spain
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Sodium Glucose Co-transporter 2 Inhibitors and Heart Failure. Am J Cardiol 2019; 124:1790-1796. [PMID: 31627834 DOI: 10.1016/j.amjcard.2019.08.038] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 08/25/2019] [Accepted: 08/30/2019] [Indexed: 01/18/2023]
Abstract
Sodium-glucose co-transporter 2 (SGLT2) receptors are primarily located in the proximal convoluted tubule of the nephron. These receptors are responsible for almost 90% to 95% of tubular reabsorption of the glucose in the nephron. In patients with diabetes mellitus, due to upregulation of SGLT2 receptors, glucose reabsorption is further increased. The Food and Drug Administration approved SGLT2 inhibitors, such as canagliflozin, empagliflozin, dapagliflozin, and ertugliflozin, for the treatment of type 2 diabetes. In addition to their positive effect on blood glucose, additional cardioprotective and renoprotective functions have been demonstrated in major trials such as EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI-58, and CREDENCE. Unlike other antihyperglycemic drugs, reduction in hospitalization for heart failure (HF) was also seen as a class effect with this group, mechanisms of which are probably multifactorial. Subgroup analysis from these major trials indicated a reduction in progression of nephropathy and HF readmission with SGLT2 inhibitors. Although this unique property of canagliflozin was further analyzed in the CREDENCE trial, similar trials for empagliflozin (EMPERIAL-Reduced and EMPERIAL-Preserved) and dapagliflozin (DAPA-HF) are currently underway. Recently released phase III results from DAPA-HF trial indicate that dapagliflozin shows significant reduction in death due to cardiovascular causes and hospitalization in HF compared with the placebo, in both diabetics and nondiabetics. In this review article, the authors attempt to explore the possible underlying molecular mechanisms and data from existing trials pertaining to the HF related outcomes associated with SGLT2 inhibitors.
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Yaribeygi H, Simental-Mendía LE, Banach M, Bo S, Sahebkar A. The major molecular mechanisms mediating the renoprotective effects of SGLT2 inhibitors: An update. Biomed Pharmacother 2019; 120:109526. [DOI: 10.1016/j.biopha.2019.109526] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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Lo KB, Gul F, Ram P, Kluger AY, Tecson KM, McCullough PA, Rangaswami J. The Effects of SGLT2 Inhibitors on Cardiovascular and Renal Outcomes in Diabetic Patients: A Systematic Review and Meta-Analysis. Cardiorenal Med 2019; 10:1-10. [PMID: 31743918 DOI: 10.1159/000503919] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 10/02/2019] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Previous meta-analyses demonstrated the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) primarily on patients with established atherosclerotic cardiovascular disease (ASCVD), but with questionable efficacy on patients at risk of ASCVD. Additionally, evidence of beneficial cardiorenal outcomes in patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 with the CV outcomes trials remains unclear. Canagliflozin, one of the SGLT2i, has recently been studied in a large randomized controlled trial in diabetic patients with chronic kidney disease. Thus, there is a need to understand the combined outcomes on the population targeted for treatment with SGLT2i as a whole, regardless of ASCVD status. This meta-analysis will therefore assess the efficacy of SGLT2i in cardiovascular and renal outcomes in general, and in patients with eGFR under 60 mL/min/1.73 m2 in particular. METHODS We searched PubMed and Cochrane databases for randomized, placebo-controlled studies involving SGLT2i. We examined composite cardiovascular outcomes of death from cardiovascular causes, nonfatal myocardial infarctions, nonfatal stroke, and heart failure hospitalizations. Renal composite outcomes and progression of albuminuria were also analyzed. Pooled relative risks (RR) and their 95% confidence intervals (CI) were calculated using a fixed-effects model. RESULTS The search yielded a total of 252 articles. Four studies were ultimately included in the meta-analysis after exclusion of other irrelevant studies. The pooled RR (95% CI) for the composite cardiovascular outcome was 0.93 (0.87-0.99) with a number needed to treat (NNT) of 167 in the general study population and 0.89 (0.77-1.02) in patients with eGFR <60 mL/min/1.73 m2. The pooled RR for all-cause mortality was 0.9 (0.84-0.97) with NNT = 143. The pooled RR for death from cardiovascular causes alone was 0.89 (0.81-0.99) in the general population and 0.82 (0.62-1.07) in patients with eGFR <60 mL/min/1.73 m2. The pooled RR for heart failure hospitalizations was 0.71 (0.63-0.79) with NNT = 91. With respect to renal outcomes, the pooled RR for the composite renal outcome was 0.63 (0.56-0.71) with NNT = 67; this was true even in patients with eGFR <60 mL/min/1.73 m2 0.67 (0.59-0.76). Lastly, the pooled RR for progression of albuminuria was 0.80 (0.76-0.84). CONCLUSION SGLT2i are associated with significantly lower major adverse cardiovascular events, heart failure hospitalizations, and all-cause mortality. The evidence is strongest in reducing heart failure hospitalizations. However, the evidence is weaker when it comes to the population subset with eGFR <60 mL/min/1.73 m2. SGLT2i are also associated with significantly lower adverse renal events, with these effects apparent even in the population with eGFR <60 mL/min/1.73 m2.
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Affiliation(s)
- Kevin Bryan Lo
- Department of Medicine, Einstein Medical Center, Philadelphia, Pennsylvania, USA,
| | - Fahad Gul
- Department of Medicine, Einstein Medical Center, Philadelphia, Pennsylvania, USA
| | - Pradhum Ram
- Department of Cardiology, Emory University, Atlanta, Georgia, USA
| | - Aaron Y Kluger
- Baylor Heart and Vascular Institute, Dallas, Texas, USA.,Baylor Scott and White Research Institute, Dallas, Texas, USA
| | - Kristen M Tecson
- Baylor Heart and Vascular Institute, Dallas, Texas, USA.,Baylor Scott and White Research Institute, Dallas, Texas, USA.,Texas A&M College of Medicine Health Science Center, Dallas, Texas, USA
| | - Peter A McCullough
- Baylor Heart and Vascular Institute, Dallas, Texas, USA.,Texas A&M College of Medicine Health Science Center, Dallas, Texas, USA.,Baylor University Medical Center, Dallas, Texas, USA.,Baylor Heart and Vascular Hospital, Dallas, Texas, USA
| | - Janani Rangaswami
- Department of Medicine, Einstein Medical Center, Philadelphia, Pennsylvania, USA.,Sidney Kimmel College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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Korbut AI, Klimontov VV, Vinogradov IV, Romanov VV. Risk factors and urinary biomarkers of non-albuminuric and albuminuric chronic kidney disease in patients with type 2 diabetes. World J Diabetes 2019; 10:517-533. [PMID: 31798788 PMCID: PMC6885724 DOI: 10.4239/wjd.v10.i11.517] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 10/06/2019] [Accepted: 10/18/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND A number of recent studies indicate a transformation in the natural course of chronic kidney disease (CKD) in type 2 diabetes (T2D) patients: an increasing prevalence of declined renal function without proceeding to the accompanying elevation of albuminuria. It has been suggested that albuminuric and non-albuminuric CKD patterns could be different in their phenotypes and pathogenic mechanisms. AIM To identify the risk factors and biomarkers of albuminuric and non-albuminuric patterns of CKD in patients with T2D. METHODS Three hundred sixty patients with T2D duration ≥ 10 years were included in this observational cross-sectional study. The associations of a panel of demographic and clinical characteristics, complications, comorbidities, and metabolic and hematology parameters with albuminuric and non-albuminuric CKD patterns were analyzed. The urinary excretion of nephrin and podocin, two podocyte-specific markers, and WAP-four-disulfide core domain protein 2 (WFDC-2), a marker of tubulointerstitial fibrosis, was determined by ELISA in comparison with healthy controls. RESULTS Non-albuminuric CKD was associated with age ≥ 65 years (P = 0.0001), female sex (P = 0.04), diabetes duration ≥ 15 years (P = 0.0009), and the use of diuretics (P = 0.0005). Male sex (P = 0.01), smoking (P = 0.01), waist-to-hip ratio >1.0 (P = 0.01) and hemoglobin A1c (HbA1c) > 8.0% (P = 0.005) were risk factors for elevated albuminuria not accompanied by a decrease in estimated glomerular filtration rate (eGFR). Duration of diabetes ≥ 15 years and the use of calcium channel blockers were risk factors for albuminuria with decreased eGFR (both P = 0.01). In multivariate logistic regression analysis, age, HbA1c, female sex and diuretics were significant predictors for reduced eGFR, while waist-to-hip ratio, HbA1c and male sex were associated with elevated urinary albumin-to-creatinine ratio (UACR). Excretion of nephrin and podocin was increased in patients with albuminuria, regardless of decline in renal function (P < 0.001), correlating positively with UACR. The urinary excretion of WFDC-2 was markedly higher in men than in women (P < 0.000001). Men with T2D demonstrated increased WFDC-2 levels independently of the CKD pattern (all P < 0.05). In T2D women, WFDC-2 excretion was increased in those with reduced renal function (P ≤ 0.01), correlating negatively with eGFR. CONCLUSION The data provide further evidence that albuminuric and non-albuminuric CKD phenotypes correspond to different pathways of diabetic kidney disease progression.
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Affiliation(s)
- Anton I Korbut
- Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL – Branch of IC&G SB RAS), Novosibirsk 630060, Russia
| | - Vadim V Klimontov
- Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL – Branch of IC&G SB RAS), Novosibirsk 630060, Russia
| | - Ilya V Vinogradov
- Clinical Laboratory, “MBU-Technology” ltd., Novosibirsk 630090, Russia
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Clegg LE, Penland RC, Bachina S, Boulton DW, Thuresson M, Heerspink HJL, Gustavson S, Sjöström CD, Ruggles JA, Hernandez AF, Buse JB, Mentz RJ, Holman RR. Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial. Cardiovasc Diabetol 2019; 18:138. [PMID: 31640705 PMCID: PMC6805385 DOI: 10.1186/s12933-019-0942-x] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 10/05/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes. METHODS In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses. RESULTS In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39-1.17) and EQW alone (0.85, 0.48-1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16-0.90) and compared with EQW (0.41, 0.17-0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94-2.94 mL/min/1.73 m2/year) and EQW alone (+ 2.38, 1.40-3.35 mL/min/1.73 m2/year). CONCLUSIONS This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010.
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Affiliation(s)
- Lindsay E Clegg
- Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, 1 MedImmune Way, Gaithersburg, MD, 20878, USA.
| | - Robert C Penland
- Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Boston, USA
| | - Srinivas Bachina
- Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Boston, USA
| | - David W Boulton
- Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, 1 MedImmune Way, Gaithersburg, MD, 20878, USA
| | | | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | | | | | - Adrian F Hernandez
- Duke University and Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA
| | - John B Buse
- University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Robert J Mentz
- Duke University and Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA
| | - Rury R Holman
- Diabetes Trials Unit, University of Oxford, Oxford, UK
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Fishman B, Shlomai G, Twig G, Derazne E, Tenenbaum A, Fisman EZ, Leiba A, Grossman E. Renal glucosuria is associated with lower body weight and lower rates of elevated systolic blood pressure: results of a nationwide cross-sectional study of 2.5 million adolescents. Cardiovasc Diabetol 2019; 18:124. [PMID: 31554505 PMCID: PMC6760097 DOI: 10.1186/s12933-019-0929-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 09/17/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Gene coding mutations found in sodium glucose co-transporters (SGLTs) are known to cause renal glucosuria. SGLT2 inhibitors have recently been shown to be effective hypoglycemic agents as well as possessing cardiovascular and renal protective properties. These beneficial effects have to some extent, been attributed to weight loss and reduced blood pressure. The aim of the current study was to evaluate the prevalence of renal glucosuria amongst a large cohort of Israeli adolescents and to investigate whether renal glucosuria is associated with lower body weight and lower blood pressure values. METHODS Medical and socio-demographic data were collected from the Israeli Defense Force's conscription center's database. A cross-sectional study to evaluate the association between conscripts diagnosed as overweight [BMI percentiles of ≥ 85 and < 95 and obesity (≥ 95 BMI percentile)] and afflicted with renal glucosuria was conducted. In addition, we assessed the association of renal glucosuria with elevated diastolic and systolic blood pressure. Multinomial regression models were used. RESULTS The final study cohort comprised 2,506,830 conscripts of whom 1108 (0.044%) were diagnosed with renal glucosuria, unrelated to diabetes mellitus, with males twice as affected compared to females. The adjusted odds ratio for overweight and obesity was 0.66 (95% CI 0.50-0.87) and 0.62 (95% CI 0.43-0.88), respectively. Adolescents afflicted with renal glucosuria were also less likely to have an elevated systolic blood pressure of 130-139 mmHg with an adjusted odds ratio of 0.74 (95% CI 0.60-0.90). CONCLUSIONS Renal glucosuria is associated with lower body weight and obesity as well as with lower rates of elevated systolic blood pressure.
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Affiliation(s)
- Boris Fishman
- Israel Defense Forces, Medical Corps, Tel Hashomer, Ramat Gan, Israel
- Internal Medicine D and Hypertension Unit, Sheba Medical Center, 2 Derech Sheba, Migdal Ishpuz, 1st Floor, Tel Hashomer, 5265601, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel
| | - Gadi Shlomai
- Internal Medicine D and Hypertension Unit, Sheba Medical Center, 2 Derech Sheba, Migdal Ishpuz, 1st Floor, Tel Hashomer, 5265601, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel
- The Institute of Endocrinology, Sheba Medical Center, Tel Hashomer, 5265601, Ramat Gan, Israel
| | - Gilad Twig
- Israel Defense Forces, Medical Corps, Tel Hashomer, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel
- Department of Military Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Estela Derazne
- Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel
| | - Alexander Tenenbaum
- Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel
- Cardiac Rehabilitation Institute, Sheba Medical Center, Tel Hashomer, 5265601, Ramat Gan, Israel
| | - Enrique Z Fisman
- Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel
| | - Adi Leiba
- Israel Defense Forces, Medical Corps, Tel Hashomer, Ramat Gan, Israel
- Division of Nephrology and Hypertension, Assuta Ashdod Academic Medical Center, 7747629, Ashdod, Israel
- Faculty of Health sciences, Ben Gurion University, Beer Sheva, Israel
- Department of Medicine, Mount Auburn Hospital, 330 Mt Auburn St, Cambridge, MA, 02138, USA
- Department of Medicine, Harvard Medical School, Boston, USA
| | - Ehud Grossman
- Internal Medicine D and Hypertension Unit, Sheba Medical Center, 2 Derech Sheba, Migdal Ishpuz, 1st Floor, Tel Hashomer, 5265601, Ramat Gan, Israel.
- Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel.
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Gutierrez MDM, Mateo MG, Corbacho N, Vidal F, Domingo P. Drug-drug interactions when treating HIV-related metabolic disorders. Expert Opin Drug Metab Toxicol 2019; 15:787-802. [PMID: 31512529 DOI: 10.1080/17425255.2019.1667334] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Introduction: Drug-drug interactions (DDI) between antiretroviral drugs and drugs for the treatment of metabolic disturbances in people living with human immunodeficiency virus (HIV) (PLWH) have represented a problem of paramount importance in the recent times. The problem has been mainly driven by sharing common metabolizing pathways. This problem has classically been worsened by the frequent use of pharmacokinetic boosters to enhance protease inhibitors and some integrase inhibitors plasma levels. Areas covered: This article focuses on the interactions between antiretroviral drugs and those drugs used to treat metabolic disturbances which frequently appear in PLWH. These include dyslipidemia, diabetes mellitus, hyperuricemia, and finally, drugs for the treatment of overweight and clinical obesity. References from PubMed, Embase, or Web of Science, among others, were reviewed. Expert opinion: The advent of safer drugs, in terms of DDI, in the antiretroviral and the metabolic field,such as non-boosted antiretrovirals and drugs with divergent metabolizing paths. Besides, learning by the caregivers on how to decrease and manage DDI, together with the extensive use of online updated DDI databases, has undoubtedly minimized the problem. The foreseeable increase in the burden of HIV-associated comorbidities and their associated treatments anticipates further complexities in the management of DDI in PLWH.
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Affiliation(s)
- Maria Del Mar Gutierrez
- Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, Institut de Recerca del Hospital de la Santa Creu i Sant Pau , Barcelona , Spain
| | - Mª Gracia Mateo
- Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, Institut de Recerca del Hospital de la Santa Creu i Sant Pau , Barcelona , Spain
| | - Noemí Corbacho
- Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, Institut de Recerca del Hospital de la Santa Creu i Sant Pau , Barcelona , Spain
| | - Francesc Vidal
- HIV Infection Unit, Department of Internal Medicine, Hospital Universitari Joan XXIII, Institut de Recerca Rovira i Virgili , Tarragona , Spain
| | - Pere Domingo
- Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, Institut de Recerca del Hospital de la Santa Creu i Sant Pau , Barcelona , Spain
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Kinguchi S, Wakui H, Ito Y, Kondo Y, Azushima K, Osada U, Yamakawa T, Iwamoto T, Yutoh J, Misumi T, Aoki K, Yasuda G, Yoshii T, Yamada T, Ono S, Shibasaki-Kurita T, Hosokawa S, Orime K, Hanaoka M, Sasaki H, Inazumi K, Yamada T, Kobayashi R, Ohki K, Haruhara K, Kobayashi Y, Yamanaka T, Terauchi Y, Tamura K. Improved home BP profile with dapagliflozin is associated with amelioration of albuminuria in Japanese patients with diabetic nephropathy: the Yokohama add-on inhibitory efficacy of dapagliflozin on albuminuria in Japanese patients with type 2 diabetes study (Y-AIDA study). Cardiovasc Diabetol 2019; 18:110. [PMID: 31455298 PMCID: PMC6710883 DOI: 10.1186/s12933-019-0912-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 08/12/2019] [Indexed: 12/12/2022] Open
Abstract
Background The Y-AIDA study was designed to investigate the renal- and home blood pressure (BP)-modulating effects of add-on dapagliflozin treatment in Japanese individuals with type 2 diabetes mellitus (T2DM) and albuminuria. Methods We conducted a prospective, multicenter, single-arm study. Eighty-six patients with T2DM, HbA1c 7.0–10.0%, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine (gCr) were enrolled, and 85 of these patients were administered add-on dapagliflozin for 24 weeks. The primary and key secondary endpoints were change from baseline in the natural logarithm of UACR over 24 weeks and change in home BP profile at week 24. Results Baseline median UACR was 181.5 mg/gCr (interquartile range 47.85, 638.0). Baseline morning, evening, and nocturnal home systolic/diastolic BP was 137.6/82.7 mmHg, 136.1/79.3 mmHg, and 125.4/74.1 mmHg, respectively. After 24 weeks, the logarithm of UACR decreased by 0.37 ± 0.73 (P < 0.001). In addition, changes in morning, evening, and nocturnal home BP from baseline were as follows: morning systolic/diastolic BP − 8.32 ± 11.42/− 4.18 ± 5.91 mmHg (both P < 0.001), evening systolic/diastolic BP − 9.57 ± 12.08/− 4.48 ± 6.45 mmHg (both P < 0.001), and nocturnal systolic/diastolic BP − 2.38 ± 7.82/− 1.17 ± 5.39 mmHg (P = 0.0079 for systolic BP, P = 0.0415 for diastolic BP). Furthermore, the reduction in UACR after 24 weeks significantly correlated with an improvement in home BP profile, but not with changes in other variables, including office BP. Multivariate linear regression analysis also revealed that the change in morning home systolic BP was a significant contributor to the change in log-UACR. Conclusions In Japanese patients with T2DM and diabetic nephropathy, dapagliflozin significantly improved albuminuria levels and the home BP profile. Improved morning home systolic BP was associated with albuminuria reduction. Trial registration The study is registered at the UMIN Clinical Trials Registry (UMIN000018930; http://www.umin.ac.jp/ctr/index-j.htm). The study was conducted from July 1, 2015 to August 1, 2018. Electronic supplementary material The online version of this article (10.1186/s12933-019-0912-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sho Kinguchi
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Hiromichi Wakui
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
| | - Yuzuru Ito
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Yoshinobu Kondo
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Kengo Azushima
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore
| | - Uru Osada
- Department of Diabetes and Endocrinology, Saiseikai Yokohama South Hospital, Yokohama, Japan
| | - Tadashi Yamakawa
- Department of Endocrinology and Diabetes, Yokohama City University Center Hospital, Yokohama, Japan
| | - Tamio Iwamoto
- Department of Nephrology and Hypertension, Saiseikai Yokohama South Hospital, Yokohama, Japan
| | - Jun Yutoh
- Department of Nephrology and Hypertension, Yokohama Minami Kyousai Hospital, Yokohama, Japan
| | - Toshihiro Misumi
- Department of Biostatistics and Epidemiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kazutaka Aoki
- Department of Internal Medicine, Kanagawa Dental University, Yokosuka, Japan
| | - Gen Yasuda
- Department of Nephrology and Hypertension, Yokohama City University Center Hospital, Yokohama, Japan
| | - Taishi Yoshii
- Department of Endocrinology and Metabolism, Yokohama Minami Kyousai Hospital, Yokohama, Japan
| | - Takayuki Yamada
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Syuji Ono
- Department of Nephrology and Hypertension, Saiseikai Yokohama South Hospital, Yokohama, Japan
| | - Tomoko Shibasaki-Kurita
- Department of Nephrology and Hypertension, Saiseikai Yokohama South Hospital, Yokohama, Japan
| | - Saho Hosokawa
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Kazuki Orime
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Masaaki Hanaoka
- Department of Nephrology and Hypertension, Saiseikai Yokohama South Hospital, Yokohama, Japan
| | - Hiroto Sasaki
- Department of Diabetes and Endocrinology, Saiseikai Yokohama South Hospital, Yokohama, Japan
| | - Kohji Inazumi
- Department of Diabetes and Endocrinology, Saiseikai Yokohama South Hospital, Yokohama, Japan
| | - Taku Yamada
- Department of Diabetes and Endocrinology, Saiseikai Yokohama South Hospital, Yokohama, Japan
| | - Ryu Kobayashi
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Kohji Ohki
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Kotaro Haruhara
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Yusuke Kobayashi
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.,Center for Novel and Exploratory Clinical Trials (Y-NEXT), Yokohama City University, Yokohama, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics and Epidemiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
| | - Kouichi Tamura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
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48
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Shepard BD. Sex differences in diabetes and kidney disease: mechanisms and consequences. Am J Physiol Renal Physiol 2019; 317:F456-F462. [PMID: 31241989 DOI: 10.1152/ajprenal.00249.2019] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Type 1 and type 2 diabetes, along with their accompanying hyperglycemia, are associated with a multitude of comorbidities including the development of diabetic kidney disease. Although the hallmarks of these metabolic disorders have been well characterized in population and animal studies, it is becoming increasingly apparent that diabetes manifests itself differently in men and women. This review summarizes the recent diabetic literature with a focus on known sex differences in clinical and preclinical studies. It explores the physiological differences of glucose handling and the development of diabetes between men and women. This review also uncovers potential mechanisms for these differences, honing in on the vital role that sex hormone signaling plays in the progression of diabetes and renal complications.
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Affiliation(s)
- Blythe D Shepard
- Department of Human Science, Georgetown University, Washington, District of Columbia
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49
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Kadowaki T, Nangaku M, Hantel S, Okamura T, von Eynatten M, Wanner C, Koitka‐Weber A. Empagliflozin and kidney outcomes in Asian patients with type 2 diabetes and established cardiovascular disease: Results from the EMPA-REG OUTCOME ® trial. J Diabetes Investig 2019; 10:760-770. [PMID: 30412655 PMCID: PMC6497612 DOI: 10.1111/jdi.12971] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 10/16/2018] [Accepted: 10/18/2018] [Indexed: 12/15/2022] Open
Abstract
AIMS/INTRODUCTION In the EMPA-REG OUTCOME® trial, empagliflozin added to standard of care improved clinically relevant kidney outcomes by 39%, slowed progression of chronic kidney disease, and reduced albuminuria in patients with type 2 diabetes and established cardiovascular disease. This exploratory analysis investigated the effects of empagliflozin on the kidneys in Asian patients. MATERIALS AND METHODS Participants in the EMPA-REG OUTCOME® trial were randomized (1:1:1) to empagliflozin 10 mg, 25 mg or a placebo. In patients of Asian race, we analyzed incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine, initiation of renal-replacement therapy or renal death) and its components, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio changes, and renal safety. RESULTS Of 7,020 treated patients, 1,517 (26.1%) were Asian. In this subgroup, consistent with the overall trial population, empagliflozin reduced the risk of incident or worsening nephropathy (hazard ratio 0.64, 95% confidence interval 0.49-0.83), progression to macroalbuminuria (hazard ratio 0.64, 95% confidence interval 0.49-0.85) and the composite of doubling of serum creatinine, initiation of renal-replacement therapy or renal death (hazard ratio 0.48, 95% confidence interval 0.25-0.92). Furthermore, empagliflozin-treated participants showed slower eGFR decline versus placebo, and showed rapid urine albumin-to-creatinine ratio reduction at week 12, maintained through week 164, with effects most pronounced in those with baseline microalbuminuria or macroalbuminuria. The kidney safety profile of empagliflozin in the Asian subgroup was similar to the overall trial population. CONCLUSIONS In Asian patients from the EMPA-REG OUTCOME® trial, empagliflozin improved kidney outcomes, slowed eGFR decline and lowered albuminuria versus placebo, consistent with the overall trial population findings.
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Affiliation(s)
| | - Masaomi Nangaku
- Graduate School of MedicineThe University of TokyoTokyoJapan
| | - Stefan Hantel
- Boehringer Ingelheim International GmbHBiberachGermany
| | | | | | | | - Audrey Koitka‐Weber
- Boehringer Ingelheim International GmbHIngelheimGermany
- Department of MedicineWürzburg University ClinicWürzburgGermany
- Department of DiabetesCentral Clinical SchoolMonash UniversityMelbourneVictoriaAustralia
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50
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Schork A, Saynisch J, Vosseler A, Jaghutriz BA, Heyne N, Peter A, Häring HU, Stefan N, Fritsche A, Artunc F. Effect of SGLT2 inhibitors on body composition, fluid status and renin-angiotensin-aldosterone system in type 2 diabetes: a prospective study using bioimpedance spectroscopy. Cardiovasc Diabetol 2019; 18:46. [PMID: 30953516 PMCID: PMC6451223 DOI: 10.1186/s12933-019-0852-y] [Citation(s) in RCA: 155] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 03/29/2019] [Indexed: 12/25/2022] Open
Abstract
Background SGLT2-inhibitors are potent antihyperglycemic drugs for patients with type 2 diabetes and have been shown to reduce body weight. However, it is unclear which body compartments are reduced and to what extent. Methods In this longitudinal observational study, we analyzed the body composition of 27 outpatients with type 2 diabetes mellitus during the first week and up to 6 months after initiation of treatment with SGLT2-inhibitors (n = 18 empagliflozin, n = 9 dapagliflozin) using bioimpedance spectroscopy (BCM, Fresenius). Fluid status of hypertensive patients taking medication with hydrochlorothiazide (n = 14) and healthy persons (n = 16) were analyzed for comparison. Results At 6 months, HbA1c decreased by 0.8% (IQR 2.3; 0.4), body weight and BMI by 2.6 kg (1.5; 9.3) and 0.9 kg/m2 (0.4; 3.3), respectively. Bioimpedance spectroscopy revealed significant decrease in adipose tissue mass and fat tissue index while lean tissue parameters remained stable. Overhydration (OH) and extracellular water (ECW) decreased by − 0.5 L/1.73 m2 (− 0.1; − 0.9) and − 0.4 L/1.73 m2 (− 0.1; − 0.8) at day 3, respectively, and returned to the initial value after 3 and 6 months. Plasma renin activity increased by 2.1-fold (0.5; 3.6) at 1 month and returned to the initial level at month 3 and 6. Fluid status of patients with SGLT2 inhibitors after 6 months showed no difference from that of hypertensive patients taking hydrochlorothiazide or healthy persons. Conclusions Body weight reduction under the treatment with SGLT2-inhibitors is caused by reduction of adipose tissue mass and transient loss of extracellular fluid, which is accompanied by upregulation of renin–angiotensin–aldosterone system (RAAS). Permanent loss of extracellular water does not occur under SGLT2 inhibition. Electronic supplementary material The online version of this article (10.1186/s12933-019-0852-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Anja Schork
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str.10, 72076, Tübingen, Germany. .,Institute of Diabetes Research and Metabolic Diseases (IDM), Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany. .,German Center for Diabetes Research (DZD), Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.
| | - Janine Saynisch
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str.10, 72076, Tübingen, Germany
| | - Andreas Vosseler
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str.10, 72076, Tübingen, Germany.,Institute of Diabetes Research and Metabolic Diseases (IDM), Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.,German Center for Diabetes Research (DZD), Otfried-Müller-Strasse 10, 72076, Tübingen, Germany
| | - Benjamin Assad Jaghutriz
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str.10, 72076, Tübingen, Germany.,Institute of Diabetes Research and Metabolic Diseases (IDM), Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.,German Center for Diabetes Research (DZD), Otfried-Müller-Strasse 10, 72076, Tübingen, Germany
| | - Nils Heyne
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str.10, 72076, Tübingen, Germany.,Institute of Diabetes Research and Metabolic Diseases (IDM), Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.,German Center for Diabetes Research (DZD), Otfried-Müller-Strasse 10, 72076, Tübingen, Germany
| | - Andreas Peter
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str.10, 72076, Tübingen, Germany.,Institute of Diabetes Research and Metabolic Diseases (IDM), Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.,German Center for Diabetes Research (DZD), Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.,Department for Diagnostic Laboratory Medicine, Institute for Clinical Chemistry and Pathobiochemistry, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str.10, 72076, Tübingen, Germany.,Institute of Diabetes Research and Metabolic Diseases (IDM), Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.,German Center for Diabetes Research (DZD), Otfried-Müller-Strasse 10, 72076, Tübingen, Germany
| | - Norbert Stefan
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str.10, 72076, Tübingen, Germany.,Institute of Diabetes Research and Metabolic Diseases (IDM), Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.,German Center for Diabetes Research (DZD), Otfried-Müller-Strasse 10, 72076, Tübingen, Germany
| | - Andreas Fritsche
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str.10, 72076, Tübingen, Germany.,Institute of Diabetes Research and Metabolic Diseases (IDM), Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.,German Center for Diabetes Research (DZD), Otfried-Müller-Strasse 10, 72076, Tübingen, Germany
| | - Ferruh Artunc
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str.10, 72076, Tübingen, Germany.,Institute of Diabetes Research and Metabolic Diseases (IDM), Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany.,German Center for Diabetes Research (DZD), Otfried-Müller-Strasse 10, 72076, Tübingen, Germany
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