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Dhoop S, Ghazaleh S, Roberts L, Shehada M, Patel M, Smith WL, Rabeeah S, Sawaf B, Vadehra P, Hart B, Hassan M. Sodium-Glucose Cotransporter-2 Inhibitors in Liver Cirrhosis: A Systematic Review of Their Role in Ascites Management, Slowing Disease Progression, and Safety. Int J Mol Sci 2025; 26:4781. [PMID: 40429923 PMCID: PMC12112422 DOI: 10.3390/ijms26104781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Revised: 05/12/2025] [Accepted: 05/14/2025] [Indexed: 05/29/2025] Open
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) are widely used for type 2 diabetes mellitus (T2DM), conferring cardiovascular and renal benefits with evidence supporting their role in metabolic-associated steatotic liver disease (MASLD), the fastest rising etiology for liver cirrhosis. Our study collects and synthesizes all available data on SGLT2I use in liver cirrhosis to summarize their potential benefits and risks. We systematically reviewed the literature on SGLT2I use in adults with cirrhosis, focusing on 6 outcome domains, including ascites reduction, disease progression, hemodynamics, acute kidney injury (AKI), electrolyte abnormalities, and infection risk. We identified 16 studies: compensated (n = 5), decompensated (n = 3), and refractory ascites (n = 8). All studies of decompensated cirrhosis (n = 11) reported ascites reduction. Most studies (7 of 9) indicated SGLT2Is slowed disease progression by reducing clinical decompensation (n = 4) or improving laboratory markers (n = 3). A minority of studies revealed safety concerns with 2 of 9 studies showing evidence of hemodynamic instability and acute kidney injury (AKI), 2 out of 13 for electrolyte abnormalities, and 2 out of 5 for infection risk. Current evidence strongly supports SGLT2Is for refractory ascites management and suggests potential benefits in slowing progression across cirrhosis severities. Longer-term prospective trials in patients with non-refractory decompensated cirrhosis and real-world safety data are essential to clarify and potentially expand the role of SGLT2Is in cirrhosis management.
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Affiliation(s)
- Sudheer Dhoop
- Department of Internal Medicine, The University of Toledo, 3333 Glendale Ave., Toledo, OH 43614, USA (B.S.)
| | - Sami Ghazaleh
- Division of Gastroenterology and Hepatology, The University of Toledo, 3333 Glendale Ave., Toledo, OH 43614, USA
| | - Luke Roberts
- College of Medicine and Life Sciences, The University of Toledo, 3000 Arlington Ave., Toledo, OH 43614, USA
| | - Mohammed Shehada
- Department of Internal Medicine, The University of Toledo, 3333 Glendale Ave., Toledo, OH 43614, USA (B.S.)
| | - Manthanbhai Patel
- Department of Internal Medicine, The University of Toledo, 3333 Glendale Ave., Toledo, OH 43614, USA (B.S.)
| | - Wade-Lee Smith
- University Library, The University of Toledo, 2801 W. Bancroft St., Toledo, OH 43606, USA
| | - Sana Rabeeah
- Department of Internal Medicine, The University of Toledo, 3333 Glendale Ave., Toledo, OH 43614, USA (B.S.)
| | - Bisher Sawaf
- Department of Internal Medicine, The University of Toledo, 3333 Glendale Ave., Toledo, OH 43614, USA (B.S.)
| | - Priya Vadehra
- Department of Biological Sciences, Wayne State University, 4841 Cass Ave., Detroit, MI 48201, USA;
| | - Benjamin Hart
- Division of Gastroenterology and Hepatology, The University of Toledo, 3333 Glendale Ave., Toledo, OH 43614, USA
| | - Mona Hassan
- Division of Gastroenterology and Hepatology, The University of Toledo, 3333 Glendale Ave., Toledo, OH 43614, USA
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Liu S, Chen W, Zhao Y, Ma S, Shi B, Guo H. SGLT2 inhibitor in a type 2 diabetes mellitus patient coexisted with central diabetes insipidus following hyperosmolar hyperglycemic state. BMC Endocr Disord 2025; 25:112. [PMID: 40264121 PMCID: PMC12013166 DOI: 10.1186/s12902-025-01924-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 04/04/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND Central diabetes insipidus (CDI) is a rare complication following a hyperglycemic hyperosmolar state (HHS) in patients with type 2 diabetes mellitus (T2DM). The coexistence of T2DM and CDI can lead to diagnostic challenges, particularly when the patients present with persistent hypernatremia without a sense of thirst. CASE PRESENTATION This case report describes a young woman with T2DM and HHS who developed persistent hypernatremia without thirst. The diagnosis of CDI was delayed until she exhibited polydipsia, consuming up to 10 L of water per day, following the administration of dapagliflozin for glucose control. Initially, the low specific gravity of urine was not evident during dapagliflozin treatment. However, after discontinuing dapagliflozin for 48 h, CDI was confirmed through a water deprivation test, which revealed polyuria with low urine specific gravity and osmolality. The patient was successfully treated with oral desmopressin. CONCLUSIONS This case highlights that SGLT2 inhibitors, such as dapagliflozin, may accelerate polyuria and alter urine osmolality by inhibiting glucose and sodium reabsorption in the proximal tubular. Therefore, it is crucial to discontinue SGLT2 inhibitors when CDI is suspected or diagnosed.
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Affiliation(s)
- Shu Liu
- Department of Endocrinology, the First Affiliated Hospital of Xian Jiaotong University, Yanta West Road 277, Xi'an, Shaanxi, China
| | - Wenqiang Chen
- Department of Endocrinology, the First Affiliated Hospital of Xian Jiaotong University, Yanta West Road 277, Xi'an, Shaanxi, China
| | - Yanru Zhao
- Department of Endocrinology, the First Affiliated Hospital of Xian Jiaotong University, Yanta West Road 277, Xi'an, Shaanxi, China
| | - Shaohui Ma
- Department of Medical Imaging, the First Affiliated Hospital of Xian Jiaotong University, Yanta West Road 277, Xi'an, Shaanxi, China
| | - Bingyin Shi
- Department of Endocrinology, the First Affiliated Hospital of Xian Jiaotong University, Yanta West Road 277, Xi'an, Shaanxi, China
| | - Hui Guo
- Department of Endocrinology, the First Affiliated Hospital of Xian Jiaotong University, Yanta West Road 277, Xi'an, Shaanxi, China.
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Hirose T, Takagi H, Kuno M, Sasaki T, Taki K, Ito Y, Miyata T, Kobayashi T, Sugiyama M, Onoue T, Hagiwara D, Iwama S, Suga H, Banno R, Arima H. Dapagliflozin increased pancreatic beta cell proliferation and insulinogenic index in mice fed a high-fat and high-sodium chloride diet. Biochem Biophys Res Commun 2025; 749:151364. [PMID: 39855047 DOI: 10.1016/j.bbrc.2025.151364] [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: 12/17/2024] [Revised: 01/17/2025] [Accepted: 01/19/2025] [Indexed: 01/27/2025]
Abstract
People in Eastern Asia, including Japan, traditionally consume higher amounts of sodium chloride than in the United States and Western Europe, and it is common knowledge that impaired insulin secretion-rather than insulin resistance-is highly prevalent in Asian people who have diabetes mellitus. We previously reported that mice fed a high-fat and high-sodium chloride (HFHS) diet had a relatively lower degree of obesity than mice fed a high-fat diet, but had a comparatively impaired insulin secretion. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to dampen down the sympathetic nervous system, which reportedly is activated by a high-sodium chloride diet. In this study, we examined the effects of dapagliflozin, a SGLT2 inhibitor, on glucose metabolism and insulin secretion in mice fed a HFHS diet. C57BL6/J mice were fed a HFHS diet for 6 weeks and subsequently divided into two treatment groups fed: (1) a HFHS diet mixed with dapagliflozin for up to 3 weeks (HFHS + Da) and (2) a HFHS diet without dapagliflozin (HFHS). Dapagliflozin improved glucose tolerance and the insulinogenic index accompanied by increased pancreatic beta cell proliferation. Furthermore, dapagliflozin decreased both the tyrosine hydroxylase-positive area in pancreatic islets and catecholamine excretion in urine. Our results suggest that dapagliflozin improved insulin secretion by suppressing sympathetic nerve activation in mice fed a HFHS diet.
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Affiliation(s)
- Tomonori Hirose
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Hiroshi Takagi
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan; Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8602, Japan.
| | - Mitsuhiro Kuno
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Tomoyuki Sasaki
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Keigo Taki
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Yoshihiro Ito
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Takashi Miyata
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Tomoko Kobayashi
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Mariko Sugiyama
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Takeshi Onoue
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Daisuke Hagiwara
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Shintaro Iwama
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Hidetaka Suga
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
| | - Ryoichi Banno
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan; Research Center of Health, Physical Fitness and Sports, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan
| | - Hiroshi Arima
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Japan
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Xiong SX, Huang LJ, Liu HS, Zhang XX, Li M, Cui YB, Shao C, Hu XL. Dapagliflozin exerts anti-apoptotic effects by mitigating macrophage polarization via modulation of the phosphoinositide 3-kinase/protein kinase B signaling pathway. World J Diabetes 2025; 16:97287. [PMID: 39959262 PMCID: PMC11718488 DOI: 10.4239/wjd.v16.i2.97287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 10/13/2024] [Accepted: 11/22/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND Macrophages are central to the orchestration of immune responses, inflammatory processes, and the pathogenesis of diabetic complications. The dynamic polarization of macrophages into M1 and M2 phenotypes critically modulates inflammation and contributes to the progression of diabetic nephropathy. Sodium-glucose cotransporter 2 inhibitors such as dapagliflozin, which are acclaimed for their efficacy in diabetes management, may influence macrophage polarization, thereby ameliorating diabetic nephropathy. This investigation delves into these mechanistic pathways, aiming to elucidate novel therapeutic strategies for diabetes. AIM To investigate the inhibitory effect of dapagliflozin on macrophage M1 polarization and apoptosis and to explore its mechanism of action. METHODS We established a murine model of type 2 diabetes mellitus and harvested peritoneal macrophages following treatment with dapagliflozin. Concurrently, the human monocyte cell line cells were used for in vitro studies. Macrophage viability was assessed in a cell counting kit 8 assay, whereas apoptosis was evaluated by Annexin V/propidium iodide staining. Protein expression was examined through western blotting, and the expression levels of macrophage M1 surface markers, inflammatory cytokines, and apoptotic factors were quantified using flow cytometry, enzyme linked immunosorbent assay, and quantitative real-time polymerase chain reaction analyses. RESULTS Dapagliflozin attenuated M1 macrophage polarization and mitigated apoptosis in the abdominal macrophages of diabetic mice, evidenced by the downregulation of proapoptotic genes (Caspase 3), inflammatory cytokines [interleukin (IL)-6, tumor necrosis factor-α, and IL-1β], and M1 surface markers (inducible nitric oxide synthase, and cluster of differentiation 86), as well as the upregulation of the antiapoptotic gene BCL2. Moreover, dapagliflozin suppressed the expression of proteins associated with the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway (PI3K, AKT, phosphorylated protein kinase B). These observations were corroborated in vitro, where we found that the modulatory effects of dapagliflozin were abrogated by 740Y-P, an activator of the PI3K/AKT signaling pathway. CONCLUSION Dapagliflozin attenuates the polarization of macrophages toward the M1 phenotype, thereby mitigating inflammation and promoting macrophage apoptosis. These effects are likely mediated through the inhibition of the PI3K/AKT signaling pathway.
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Affiliation(s)
- Sheng-Xi Xiong
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Lin-Juan Huang
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Han-Shuang Liu
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Xiao-Xiao Zhang
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Min Li
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Yu-Bing Cui
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Chen Shao
- Department of Endocrinology, The Second Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
| | - Xiao-Lei Hu
- Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
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Del Monaco G, Amata F, Battaglia V, Panico C, Condorelli G, Pinto G. Hemodynamics in Left-Sided Cardiomyopathies. Rev Cardiovasc Med 2024; 25:455. [PMID: 39742240 PMCID: PMC11683717 DOI: 10.31083/j.rcm2512455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 08/22/2024] [Accepted: 08/29/2024] [Indexed: 01/03/2025] Open
Abstract
Cardiomyopathies, historically regarded as rare, are increasingly recognized due to advances in imaging diagnostics and heightened clinical focus. These conditions, characterized by structural and functional abnormalities of the myocardium, pose significant challenges in both chronic and acute patient management. A thorough understanding of the hemodynamic properties, specifically the pressure-volume relationships, is essential. These relationships provide insights into cardiac function, including ventricular compliance, contractility, and overall cardiovascular performance. Despite their potential utility, pressure-volume curves are underutilized in clinical settings due to the invasive nature of traditional measurement techniques. Recognizing the dynamic nature of cardiomyopathies, with possible transitions between phenotypes, underscores the importance of continuous monitoring and adaptive therapeutic strategies. Enhanced hemodynamic evaluation can facilitate tailored treatment, potentially improving outcomes for patients with these complex cardiac conditions.
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Affiliation(s)
- Guido Del Monaco
- IRCCS (Istituto di Ricerca e Cura a Carattere Scientifico) Humanitas Research Hospital, 20089 Rozzano-Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve-Emanuele-Milan, Italy
| | - Francesco Amata
- IRCCS (Istituto di Ricerca e Cura a Carattere Scientifico) Humanitas Research Hospital, 20089 Rozzano-Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve-Emanuele-Milan, Italy
| | - Vincenzo Battaglia
- IRCCS (Istituto di Ricerca e Cura a Carattere Scientifico) Humanitas Research Hospital, 20089 Rozzano-Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve-Emanuele-Milan, Italy
| | - Cristina Panico
- IRCCS (Istituto di Ricerca e Cura a Carattere Scientifico) Humanitas Research Hospital, 20089 Rozzano-Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve-Emanuele-Milan, Italy
| | - Gianluigi Condorelli
- IRCCS (Istituto di Ricerca e Cura a Carattere Scientifico) Humanitas Research Hospital, 20089 Rozzano-Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve-Emanuele-Milan, Italy
| | - Giuseppe Pinto
- IRCCS (Istituto di Ricerca e Cura a Carattere Scientifico) Humanitas Research Hospital, 20089 Rozzano-Milan, Italy
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Gao Y, Liu X, Gao Y, Duan M, Hou B, Chen Y. Pharmacological Interventions for Cirrhotic Ascites: From Challenges to Emerging Therapeutic Horizons. Gut Liver 2024; 18:934-948. [PMID: 39205495 PMCID: PMC11565010 DOI: 10.5009/gnl240038] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 05/01/2024] [Accepted: 05/02/2024] [Indexed: 09/04/2024] Open
Abstract
Ascites is the most common complication in patients with decompensated cirrhosis. This condition results in a severely impaired quality of life, excessive healthcare use, recurrent hospitalizations and significant morbidity and mortality. While loop diuretics and mineralocorticoid receptor antagonists are commonly employed for symptom relief, our understanding of their impact on survival remains limited. A comprehensive understanding of the underlying pathophysiological mechanism of ascites is crucial for its optimal management. The renin-angiotensin-aldosterone system (RAAS) is increasingly believed to play a pivotal role in the formation of cirrhotic ascites, as RAAS overactivation leads to a reduction in urine sodium excretion then a decrease in the ability of the kidneys to excrete water. In this review, the authors provide an overview of the pathogenesis of cirrhotic ascites, the challenges associated with current pharmacologic treatments, and the previous attempts to modulate the RAAS, followed by a description of some emerging targeted RAAS agents with the potential to be used to treat ascites.
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Affiliation(s)
- Yuan Gao
- Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xin Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yunyi Gao
- School of Basic Medicine, Qingdao University, Qingdao, China
| | - Meili Duan
- Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Bing Hou
- Xenorm MedInfo Center, Beijing, China
| | - Yu Chen
- Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
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Guo S, Tong Y, Li T, Yang K, Gao W, Peng F, Zou X. Endoplasmic Reticulum Stress-Mediated Cell Death in Renal Fibrosis. Biomolecules 2024; 14:919. [PMID: 39199307 PMCID: PMC11352060 DOI: 10.3390/biom14080919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/04/2024] [Accepted: 07/25/2024] [Indexed: 09/01/2024] Open
Abstract
The endoplasmic reticulum (ER) is indispensable for maintaining normal life activities. Dysregulation of the ER function results in the accumulation of harmful proteins and lipids and the disruption of intracellular signaling pathways, leading to cellular dysfunction and eventual death. Protein misfolding within the ER disrupts its delicate balance, resulting in the accumulation of misfolded or unfolded proteins, a condition known as endoplasmic reticulum stress (ERS). Renal fibrosis, characterized by the aberrant proliferation of fibrotic tissue in the renal interstitium, stands as a grave consequence of numerous kidney disorders, precipitating a gradual decline in renal function. Renal fibrosis is a serious complication of many kidney conditions and is characterized by the overgrowth of fibrotic tissue in the glomerular and tubular interstitium, leading to the progressive failure of renal function. Studies have shown that, during the onset and progression of kidney disease, ERS causes various problems in the kidneys, a process that can lead to kidney fibrosis. This article elucidates the underlying intracellular signaling pathways modulated by ERS, delineating its role in triggering diverse forms of cell death. Additionally, it comprehensively explores a spectrum of potential pharmacological agents and molecular interventions aimed at mitigating ERS, thereby charting novel research avenues and therapeutic advancements in the management of renal fibrosis.
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Affiliation(s)
| | | | | | | | | | | | - Xiangyu Zou
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang 261053, China; (S.G.); (Y.T.); (T.L.); (K.Y.); (W.G.); (F.P.)
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Marton A, Saffari SE, Rauh M, Sun RN, Nagel AM, Linz P, Lim TT, Takase-Minegishi K, Pajarillaga A, Saw S, Morisawa N, Yam WK, Minegishi S, Totman JJ, Teo S, Teo LLY, Ng CT, Kitada K, Wild J, Kovalik JP, Luft FC, Greasley PJ, Chin CWL, Sim DKL, Titze J. Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure. J Am Coll Cardiol 2024; 83:1386-1398. [PMID: 38599715 DOI: 10.1016/j.jacc.2024.02.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 02/08/2024] [Accepted: 02/08/2024] [Indexed: 04/12/2024]
Abstract
BACKGROUND Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential. OBJECTIVES The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment. METHODS DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance. RESULTS Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor-naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51-4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98-3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77-12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: -9.1 mL/kg/d [95% CI: -14 to -4.12; P < 0.001]; late: -11.0 mL/kg/d [95% CI: -15.94 to -6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28-229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: -1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: -3.83 to 5.62]; P = 0.70). CONCLUSIONS Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518).
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Affiliation(s)
- Adriana Marton
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore; Department of Internal Medicine 4-Nephrology and Hypertension, Paracelsus Private Medical School Nuremberg, Nuremberg, Germany.
| | | | - Manfred Rauh
- Research Laboratory, Division of Paediatrics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Ruo-Ning Sun
- Clinical Imaging Research Centre, Centre for Translational Medicine, Singapore
| | - Armin M Nagel
- Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany; German Cancer Research Center (DKFZ), Division of Medical Physics in Radiology, Heidelberg, Germany
| | - Peter Linz
- Institute of Radiology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Tzy Tiing Lim
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore
| | | | | | - Sharon Saw
- Department of Laboratory Medicine, National University Hospital, Singapore
| | - Norihiko Morisawa
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore
| | - Wan Keat Yam
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore
| | - Shintaro Minegishi
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore
| | - John J Totman
- Clinical Imaging Research Centre, Centre for Translational Medicine, Singapore; Radiography and Medical Imaging Department, Fatima College of Health Sciences, Abu Dhabi, United Arab Emirates
| | - Serena Teo
- Clinical Imaging Research Centre, Centre for Translational Medicine, Singapore
| | - Louis L Y Teo
- Department of Cardiology, National Heart Centre Singapore, Singapore
| | - Choon Ta Ng
- Department of Cardiology, National Heart Centre Singapore, Singapore
| | - Kento Kitada
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Johannes Wild
- Center for Cardiology, Cardiology I, Johannes Gutenberg-University, Mainz, Germany
| | - Jean-Paul Kovalik
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore
| | - Friedrich C Luft
- Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Berlin, Germany
| | - Peter J Greasley
- Early Discovery and Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Calvin W L Chin
- Department of Cardiology, National Heart Centre Singapore, Singapore
| | - David K L Sim
- Department of Cardiology, National Heart Centre Singapore, Singapore
| | - Jens Titze
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore; III. Department of Medicine and Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Division of Nephrology, Duke University Medical Center, Durham, North Carolina, USA.
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9
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Kurozumi A, Shishido K, Yamashita T, Sato D, Uchida S, Koyama E, Tamaki Y, Hayashi T, Miyashita H, Yokoyama H, Ochiai T, Yamaguchi M, Moriyama N, Tobita K, Matsumoto T, Mizuno S, Yamanaka F, Tanaka Y, Murakami M, Takahashi S, Saito S. Sodium-Glucose Cotransporter-2 Inhibitors Stabilize Coronary Plaques in Acute Coronary Syndrome With Diabetes Mellitus. Am J Cardiol 2024; 214:47-54. [PMID: 38215815 DOI: 10.1016/j.amjcard.2023.12.056] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 12/13/2023] [Accepted: 12/27/2023] [Indexed: 01/14/2024]
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are widely used in cardiology and are effective in treating acute coronary syndrome (ACS). Their effects on unstable plaque in patients with ACS remains unclear. This study aimed to examine the effectiveness of SGLT2is in coronary plaque based on optical coherence tomography (OCT) images and the prognosis of ACS with type 2 diabetes mellitus. This retrospective study included 109 patients in the total cohort and 29 patients in the OCT cohort. Based on SGLT2i administration after ACS, the total cohort was categorized into non-SGLT2i (n = 69) and SGLT2i (n = 40) groups. The OCT cohort had 15 and 14 patients in the non-SGLT2i and SGLT2i groups, respectively. The OCT images of unstable plaque were analyzed in nonstented lesions during ACS catheterization and at the 6-month follow-up. The total cohort was assessed after 1 year for major adverse cardiovascular events, including all-cause mortality, revascularization, cerebrovascular disease, and heart failure hospitalization. SGLT2is improved unstable lesions with a significantly thicker fibrous cap (48 ± 15 μm vs 26 ± 24 μm, p = 0.005), reduced lipid arc (-29 ± 12° vs -18 ± 14°, p = 0.028), higher % decrease in total lipid arc (-35 ± 13% vs -19 ± 18%, p = 0.01), and lower major adverse cardiovascular event incidence (log-rank p = 0.023, hazard ratio 4.72 [1.08 to 20.63]) and revascularization rate (adjusted hazard ratio 6.77 [1.08 to 42.52]) than the non-SGLT2i group. In conclusion, SGLT2is can improve the markers of plaque stability and may improve the prognosis in patients with type 2 diabetes mellitus.
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Affiliation(s)
- Atsumasa Kurozumi
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Koki Shishido
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan.
| | | | - Daisuke Sato
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Syuhei Uchida
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Eiji Koyama
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Yusuke Tamaki
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Takahiro Hayashi
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Hirokazu Miyashita
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Hiroaki Yokoyama
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Tomoki Ochiai
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Masashi Yamaguchi
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Noriaki Moriyama
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Kazuki Tobita
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Takashi Matsumoto
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Shingo Mizuno
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Futoshi Yamanaka
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Yutaka Tanaka
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Masato Murakami
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Saeko Takahashi
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Shigeru Saito
- Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Japan
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10
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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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11
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Banerjee M, Maisnam I, Pal R, Mukhopadhyay S. Mineralocorticoid receptor antagonists with sodium-glucose co-transporter-2 inhibitors in heart failure: a meta-analysis. Eur Heart J 2023; 44:3686-3696. [PMID: 37605637 DOI: 10.1093/eurheartj/ehad522] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 07/12/2023] [Accepted: 08/03/2023] [Indexed: 08/23/2023] Open
Abstract
BACKGROUND AND AIMS To investigate the cardiovascular effects of sodium-glucose co-transporter-2 inhibitors (SGLT2i) with concomitant mineralocorticoid receptor antagonist (MRA) use in heart failure (HF) regardless of ejection fraction (EF) and explore the risk of MRA-associated adverse events in individuals randomized to SGLT2i vs. placebo. METHODS PubMed/MEDLINE, Web of Science, Embase, and clinical trial registries were searched for randomized controlled trials/post-hoc analyses evaluating SGLT2i in HF with or without MRA use (PROSPERO: CRD42023397129). The main outcomes were composite of first hospitalization or urgent visit for HF/cardiovascular death (HHF/CVD), HHF, and CVD. Others were all-cause mortality, composite renal and safety outcomes. Hazard ratios (HR)/risk ratios were extracted. Fixed-effects meta-analyses and subgroup analyses were performed. RESULTS Five eligible studies were included, pooling data from 21 947 people with HF (type 2 diabetes mellitus, n = 10 805). Compared to placebo, randomization to SGLT2i showed a similar reduction in HHF/CVD and HHF in people who were or were not using MRAs [HHF/CVD: hazard ratio (HR) 0.75; 95% confidence interval (CI) 0.68-0.81 vs. HR 0.79; 95% CI 0.72-0.86; P-interaction = .43; HHF: HR 0.74; 95% CI 0.67-0.83 vs. HR 0.71; 95% CI 0.63-0.80; P-interaction = .53], with a suggestion of greater relative reduction in CVD in chronic HF people randomized to SGLT2i and using MRAs irrespective of EF (HR 0.81; 95% CI 0.72-0.91 vs. HR 0.98; 95% CI 0.86-1.13; P-interaction = .034). SGLT2i reduced all-cause mortality (P-interaction = .27) and adverse renal endpoints regardless of MRA use (P-interaction = .73) despite a higher risk of volume depletion with concomitant MRAs (P-interaction = .082). SGLT2i attenuated the risk of mild hyperkalaemia (P-interaction < .001) and severe hyperkalaemia (P-interaction = .051) associated with MRA use. CONCLUSIONS MRAs did not influence SGLT2i effects on the composite of HHF/CVD, HHF or all-cause mortality; however, findings hinted at a more pronounced relative reduction in CVD in chronic HF patients regardless of EF who were randomized to SGLT2i and receiving an MRA compared to those randomized to SGLT2i and not receiving MRAs. SGLT2i attenuated the risk of MRA-associated treatment-emergent hyperkalaemia. These findings warrant further validation in well-designed randomized controlled trials.
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Affiliation(s)
- Mainak Banerjee
- Department of Endocrinology, Institute of Postgraduate Medical Education and Research, 244, AJC Bose Rd, Kolkata, West Bengal 700020, India
| | - Indira Maisnam
- Department of Endocrinology, Institute of Postgraduate Medical Education and Research, 244, AJC Bose Rd, Kolkata, West Bengal 700020, India
| | - Rimesh Pal
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Satinath Mukhopadhyay
- Department of Endocrinology, Institute of Postgraduate Medical Education and Research, 244, AJC Bose Rd, Kolkata, West Bengal 700020, India
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12
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Piko N, Bevc S, Hojs R, Ekart R. The Role of Oxidative Stress in Kidney Injury. Antioxidants (Basel) 2023; 12:1772. [PMID: 37760075 PMCID: PMC10525550 DOI: 10.3390/antiox12091772] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/13/2023] [Accepted: 09/15/2023] [Indexed: 09/29/2023] Open
Abstract
Acute kidney injury and chronic kidney disease are among the most common non-communicable diseases in the developed world, with increasing prevalence. Patients with acute kidney injury are at an increased risk of developing chronic kidney disease. One of kidney injury's most common clinical sequelae is increased cardiovascular morbidity and mortality. In recent years, new insights into the pathophysiology of renal damage have been made. Oxidative stress is the imbalance favoring the increased generation of ROS and/or reduced body's innate antioxidant defense mechanisms and is of pivotal importance, not only in the development and progression of kidney disease but also in understanding the enhanced cardiovascular risk in these patients. This article summarizes and emphasizes the role of oxidative stress in acute kidney injury, various forms of chronic kidney disease, and also in patients on renal replacement therapy (hemodialysis, peritoneal dialysis, and after kidney transplant). Additionally, the role of oxidative stress in the development of drug-related nephrotoxicity and also in the development after exposure to various environmental and occupational pollutants is presented.
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Affiliation(s)
- Nejc Piko
- Department of Dialysis, Clinic for Internal Medicine, University Medical Centre, 2000 Maribor, Slovenia;
| | - Sebastjan Bevc
- Department of Nephrology, Clinic for Internal Medicine, University Medical Centre, 2000 Maribor, Slovenia; (S.B.); (R.H.)
- Medical Faculty, University of Maribor, 2000 Maribor, Slovenia
| | - Radovan Hojs
- Department of Nephrology, Clinic for Internal Medicine, University Medical Centre, 2000 Maribor, Slovenia; (S.B.); (R.H.)
- Medical Faculty, University of Maribor, 2000 Maribor, Slovenia
| | - Robert Ekart
- Department of Dialysis, Clinic for Internal Medicine, University Medical Centre, 2000 Maribor, Slovenia;
- Medical Faculty, University of Maribor, 2000 Maribor, Slovenia
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13
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Feng B, Yu P, Yu H, Qian B, Li Y, Sun K, Shi B, Zhang N, Xu G. Therapeutic effects on the development of heart failure with preserved ejection fraction by the sodium-glucose cotransporter 2 inhibitor dapagliflozin in type 2 diabetes. Diabetol Metab Syndr 2023; 15:141. [PMID: 37386620 DOI: 10.1186/s13098-023-01116-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 06/17/2023] [Indexed: 07/01/2023] Open
Abstract
BACKGROUND Heart failure with preserved ejection fraction (HFpEF) is a common disease with high morbidity and lacks effective treatment. We investigated the protective effects of the long-term application of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin on diabetes-associated HFpEF in a rat model. Serum proteomics and metabolomics analysis were also conducted in type 2 diabetic patients with HFpEF treated with dapagliflozin. METHODS Male Zucker diabetic fatty (ZDF) rats were used as a model of diabetic cardiomyopathy. From weeks 16 to 28, animals were given a vehicle or dapagliflozin (1 mg/kg) once daily. Primary blood biochemistry indices, echocardiography, histopathology, and cardiac hemodynamics were determined during the study period. The key markers of myocardial fibrosis, nitro-oxidative stress, inflammation, apoptosis, autophagy, and AMPK/mTOR signaling were examined. Additionally, healthy controls and individuals with type 2 diabetes were enrolled and 16 serum samples from 4 groups were randomly selected. Serum proteome and metabolome changes after dapagliflozin treatment were analyzed in diabetic individuals with HFpEF. RESULTS Dapagliflozin effectively prevented the development of HFpEF in rats with diabetes by mitigating nitro-oxidative stress, pro-inflammatory cytokines, myocardial hypertrophy, and fibrosis, reducing apoptosis, and restoring autophagy through AMPK activating and mTOR pathway repressing. Proteomics and metabolomics revealed that cholesterol and high-density lipoprotein particle metabolism, nicotinate and nicotinamide metabolism, arginine biosynthesis, and cAMP and peroxisome proliferator-activated receptor (PPAR) signaling are the major disturbed pathways in HFpEF patients treated with dapagliflozin. CONCLUSION Long-term treatment with dapagliflozin significantly prevented the development of HFpEF in diabetic rats. Dapagliflozin could be a promising therapeutic strategy in managing HFpEF individuals with type 2 diabetes.
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Affiliation(s)
- Bin Feng
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, People's Republic of China
| | - Peiran Yu
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, 215008, Jiangsu, People's Republic of China
| | - Hao Yu
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, 215008, Jiangsu, People's Republic of China
| | - Buyun Qian
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, 215008, Jiangsu, People's Republic of China
| | - Yuan Li
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, 215008, Jiangsu, People's Republic of China
| | - Kangyun Sun
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, 215008, Jiangsu, People's Republic of China
| | - Bimin Shi
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, People's Republic of China
| | - Nannan Zhang
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, 215008, Jiangsu, People's Republic of China.
| | - Guidong Xu
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, 242 Guangji Road, Suzhou, 215008, Jiangsu, People's Republic of China.
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14
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Feng B, Yang F, Liu J, Sun Q, Meng R, Zhu D. Amelioration of diabetic kidney injury with dapagliflozin is associated with suppressing renal HMGB1 expression and restoring autophagy in obese mice. J Diabetes Complications 2023; 37:108409. [PMID: 36731146 DOI: 10.1016/j.jdiacomp.2023.108409] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 01/12/2023] [Accepted: 01/23/2023] [Indexed: 01/29/2023]
Abstract
Diabetic kidney disease (DKD) is a major cause of chronic and end-stage renal disease in diabetic patients. Here, we investigated protective effects and possible mechanisms of dapagliflozin on renal injury in diabetic mice. DKD mice were established by high fat diet (HFD) feeding. Half of DKD mice were randomly assigned to receive dapagliflozin treatment (200 μg/day) for 8 weeks. Renal lipid droplets, fibrosis, oxidative and endoplasmic reticulum stress were evaluated. Glomerular injury was assessed by immunohistochemistry and transmission electron microscopy. Dapagliflozin led to marked inhibition of ROS levels and endoplasmic reticulum stress in diabetic mice. HFD-induced loss of Podocin and Nephrin, and impaired podocytes were also improved with the treatment. Importantly, overexpression of HMGB1 and suppressed autophagy in the kidney were partly reversed by dapagliflozin. Therefore, we speculate that protective effects of dapagliflozin on DKD may be associated with suppression of HMGB1 expression and restoration of autophagy in the kidney.
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Affiliation(s)
- Bin Feng
- Department of Endocrinology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Fan Yang
- Department of Endocrinology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China
| | - Jie Liu
- Department of Endocrinology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China
| | - Qichao Sun
- Department of Endocrinology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China
| | - Ran Meng
- Department of Endocrinology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China.
| | - Dalong Zhu
- Department of Endocrinology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China.
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15
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Shiina K, Tomiyama H, Tanaka A, Imai T, Hisauchi I, Taguchi I, Sezai A, Toyoda S, Dohi K, Kamiya H, Kida K, Anzai T, Chikamori T, Node K. Canagliflozin independently reduced plasma volume from conventional diuretics in patients with type 2 diabetes and chronic heart failure: a subanalysis of the CANDLE trial. Hypertens Res 2023; 46:495-506. [PMID: 36380202 DOI: 10.1038/s41440-022-01085-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 09/24/2022] [Accepted: 10/03/2022] [Indexed: 11/16/2022]
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce the risk of heart failure progression and mortality rates. Moreover, osmotic diuresis induced by SGLT2 inhibition may result in an improved heart failure prognosis. Independent of conventional diuretics in patients with type 2 diabetes (T2D) and chronic heart failure, especially in patients with heart failure with preserved ejection fraction (HFpEF), it is unclear whether SGLT2i chronically reduces estimated plasma volume (ePV). As a subanalysis of the CANDLE trial, which assessed the effect of canagliflozin on N-terminal pro-brain natriuretic peptide (NT-proBNP), we examined the change (%) in ePV over 24 weeks of treatment based on the baseline level associated with diuretic usage. In the CANDLE trial, nearly all patients were clinically stable (NYHA class I-II), with approximately 70% of participants presenting a baseline phenotype of HFpEF. A total of 99 (42.5%) patients were taking diuretics (mostly furosemide) at baseline, while 134 (57.5%) were not. Relative to glimepiride, canagliflozin significantly reduced ePV without worsening renal function in patients in both groups: -4.00% vs. 1.46% (p = 0.020) for the diuretic group and -6.14% vs. 1.28% (p < 0.001) for the nondiuretic group. Furthermore, canagliflozin significantly reduced serum uric acid without causing major electrolyte abnormalities in patients in both subgroups. The long-term beneficial effect of SGLT2i on intravascular congestion could be independent of conventional diuretic therapy without worsening renal function in patients with T2D and HF (HFpEF predominantly). In addition, the beneficial effects of canagliflozin are accompanied by improved hyperuricemia without causing major electrolyte abnormalities.
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Affiliation(s)
- Kazuki Shiina
- Department of Cardiology, Tokyo Medical University, Tokyo, Japan.
| | | | - Atsushi Tanaka
- Department of Cardiovascular Medicine, Saga University, Saga, Japan
| | - Takumi Imai
- Department of Medical Statistics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Itaru Hisauchi
- Department of Cardiology, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan
| | - Isao Taguchi
- Department of Cardiology, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan
| | - Akira Sezai
- The Department of Cardiovascular Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Shigeru Toyoda
- Department of Cardiovascular Medicine, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | - Kaoru Dohi
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Haruo Kamiya
- Department of Cardiology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan
| | - Keisuke Kida
- Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Toshihisa Anzai
- Department of Cardiovascular Medicine, Hokkaido University, Sapporo, Japan
| | | | - Koichi Node
- Department of Cardiovascular Medicine, Saga University, Saga, Japan
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16
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Deng R, Jiang K, Chen F, Miao Y, Lu Y, Su F, Liang J, Qian J, Wang D, Xiang Y, Shen L. Novel cardioprotective mechanism for Empagliflozin in nondiabetic myocardial infarction with acute hyperglycemia. Biomed Pharmacother 2022; 154:113606. [PMID: 36030589 DOI: 10.1016/j.biopha.2022.113606] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/20/2022] [Accepted: 08/23/2022] [Indexed: 01/08/2023] Open
Abstract
Patients with AMI and hyperglycemia upon hospital admission exhibited poorer prognosis compared with those without hyperglycemia. It is unknown whether SGLT2 inhibitors can also improve nondiabetic myocardial infarction (MI) with acute hyperglycemia and the underlying mechanisms. Here we demonstrated that hyperglycemia patients were more likely to have worse cardiac function levels, such as with Killip III/IV during hospitalization. Glucose injection-induced nondiabetic MI accompanied by acute hyperglycemia in WT mice, manifested lower survival compared with control. A significant increase in both survival and LV function was observed when treated with empagliflozin (EMPA). In addition, EMPA attenuated fibrosis and autophagy of border cardiac tissue in mice with MI accompanied by acute hyperglycemia. Applying Beclin1+/- and NHE1 cKO mice, we found that Beclin1 deficiency improved survival. Mechanistically, EMPA had a more significant cardioprotective effect through inhibited its autophagy level by targeted Beclin1 rather than NHE1. In addition, EMPA rescued cardiomyocytes autosis induced by Tat-beclin1 or GD, conferring cardioprotection decreasing autophagic cell death. These findings provide new insights that SGLT2 inhibitor effectively ameliorates the myocardial injury in nondiabetic myocardial infarction with acute hyperglycemia through suppressing beclin1-dependent autosis rather than elusively targeting NHE1 in cardiomyocytes.
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Affiliation(s)
- Ruhua Deng
- Shanghai East Hospital, Key Laboratory of Arrhythmias of the Ministrcy of Education of China, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Kai Jiang
- Shanghai East Hospital, Key Laboratory of Arrhythmias of the Ministrcy of Education of China, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Feng Chen
- Shanghai East Hospital, Key Laboratory of Arrhythmias of the Ministrcy of Education of China, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Yutong Miao
- Department of Cardiology, Clinical Research Unit, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Yanqiao Lu
- Department of Cardiology, Clinical Research Unit, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Fanghua Su
- Shanghai East Hospital, Key Laboratory of Arrhythmias of the Ministrcy of Education of China, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Jiayi Liang
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Jie Qian
- Shanghai East Hospital, Key Laboratory of Arrhythmias of the Ministrcy of Education of China, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Dandan Wang
- Shanghai East Hospital, Key Laboratory of Arrhythmias of the Ministrcy of Education of China, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Yaozu Xiang
- Shanghai East Hospital, Key Laboratory of Arrhythmias of the Ministrcy of Education of China, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
| | - Lan Shen
- Department of Cardiology, Clinical Research Unit, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.
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17
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Yau K, Dharia A, Alrowiyti I, Cherney DZ. Prescribing SGLT2 Inhibitors in Patients with Chronic Kidney Disease: Expanding Indications and Practical Considerations. Kidney Int Rep 2022; 7:1463-1476. [PMID: 35812300 PMCID: PMC9263228 DOI: 10.1016/j.ekir.2022.04.094] [Citation(s) in RCA: 107] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/08/2022] [Accepted: 04/25/2022] [Indexed: 12/20/2022] Open
Affiliation(s)
- Kevin Yau
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Atit Dharia
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Ibrahim Alrowiyti
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - David Z.I. Cherney
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Correspondence: David Z.I. Cherney, Division of Nephrology, Department of Medicine, Toronto General Hospital, 585 University Avenue, 8N-845, Toronto, Ontario, M5G 2N2, Canada.
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18
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Shi Z, Gao F, Liu W, He X. Comparative Efficacy of Dapagliflozin and Empagliflozin of a Fixed Dose in Heart Failure: A Network Meta-Analysis. Front Cardiovasc Med 2022; 9:869272. [PMID: 35445086 PMCID: PMC9013819 DOI: 10.3389/fcvm.2022.869272] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 03/09/2022] [Indexed: 12/22/2022] Open
Abstract
Background The efficacy of dapagliflozin and empagliflozin in sodium-glucose cotransport-2 inhibitors (SGLT-2i) in patients with heart failure (HF) has been discovered. However, which drug could improve varied prognostic outcomes has not been elucidated. Hence, we compared their efficacies on the prognostic improvement of HF. Methods Databases including PubMed, EMBASE, Scopus, Google Scholars, and the Cochrane Library were searched for all related randomized controlled trials (RCTs) published from inception to 13 October 2021. Network meta-analyses were performed to generate matrices to show the effect size for pairwise comparison regarding all the interventions. Results Eventually a total of 11 RCTs were included in this study. For the primary endpoints, dapagliflozin was comparable with empagliflozin in hospitalization for HF, and empagliflozin (OR=0.70, 95%CI: 0.59-0.84) decreased the risk of exacerbation of HF over dapagliflozin. For the secondary endpoints, dapagliflozin was comparable with empagliflozin in cardiovascular (CV) death /hospitalization for HF, and for CV death, dapagliflozin (OR=0.78, 95%CI: 0.65-0.92) significantly reduced mortality over the placebo. For the tertiary endpoints, dapagliflozin (OR=0.80, 95%CI: 0.66-0.98) significantly decreased the mortality over empagliflozin in all-cause death, and neither drug significantly increased the risk of hypoglycemia. Recommendations Overall, 10 mg/day dapagliflozin may be the optimal recommendation for its premium and comprehensive effect on improving the prognosis of patients with HF compared to 10 mg/day empagliflozin.
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Affiliation(s)
| | | | | | - Xuezhi He
- Department of Cardiovascular Surgery, Dalian Municipal Central Hospital, Dalian, China
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19
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Cao Y, Li P, Li Y, Han Y. Sodium-glucose cotransporter-2 inhibitors in heart failure: an updated meta-analysis. ESC Heart Fail 2022; 9:1942-1953. [PMID: 35338608 PMCID: PMC9065870 DOI: 10.1002/ehf2.13905] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 02/10/2022] [Accepted: 03/07/2022] [Indexed: 01/10/2023] Open
Abstract
Aims We aimed to examine efficacy and safety outcomes of sodium‐glucose cotransporter‐2 inhibitor (SGLT2i) for the treatment of heart failure (HF), especially in patients with heart failure with preserved ejection fraction (HFpEF). Methods and results PubMed, Web of Science, and Cochrane Library were searched to identify randomized controlled trials comparing SGLT2i vs. placebo in HF patients. A total of 10 studies with 23 852 HF patients were eventually included. Compared with placebo, SGLT2i is associated with a lower incidence of composite of first hospitalization for heart failure (HHF) or cardiovascular death (CV death) [hazard ratio (HR) = 0.76 95% confidence interval (CI) = 0.71–0.81], which is consistent regardless of the diabetes status, type of gliflozines used, and follow‐up duration. SGLT2i can reduce the risk of total HHF or CV death (HR = 0.74, 95%CI = 0.68–0.81), first HHF (HR = 0.69, 95%CI = 0.64–0.75), CV death (HR = 0.88, 95%CI = 0.80–0.96), any death (HR = 0.90, 95%CI = 0.83–0.97), and any serious events (HR = 0.90, 95%CI = 0.87–0.93) in HF patients, at the cost of increased risk of urinary tract infections (risk ratio = 1.17, 95%CI = 1.03–1.33). In HFpEF patients, SGLT2i is associated with a significant reduction of composite of first HHF or CV death (HR = 0.81, 95%CI = 0.73–0.91), first HHF (HR = 0.71, 95%CI = 0.62–0.82), and total HHF or CV death (HR = 0.61, 95%CI = 0.43–0.86). Conclusions Sodium‐glucose cotransporter‐2 inhibitor contributed to better efficacy outcomes in overall HF patients and showed an inspiring breakthrough in the treatment of HFpEF.
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Affiliation(s)
- Yang Cao
- The Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi'an, China.,The Department of Cardiology, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, 110016, China
| | - Pengxiao Li
- The Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi'an, China.,The Department of Cardiology, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, 110016, China
| | - Yi Li
- The Department of Cardiology, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, 110016, China
| | - Yaling Han
- The Department of Cardiology, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, 110016, China
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20
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Scheen AJ, Delanaye P. Understanding the protective effects of SGLT2 inhibitors in type 2 diabetes patients with chronic kidney disease. Expert Rev Endocrinol Metab 2022; 17:35-46. [PMID: 34908510 DOI: 10.1080/17446651.2022.2014322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 11/30/2021] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Sodium-glucose co-transporter type 2 inhibitors (SGLT2is) were developed as glucose-lowering agents for the management of type 2 diabetes (T2D). Unexpectedly, they showed a significant reduction in hospitalization for heart failure and hard renal outcomes in patients with and without T2D. Underlying mechanisms remain a matter of debate. AREAS COVERED We summarize the protective renal effects of SGLT2is in patients with cardiovascular disease, chronic kidney disease (CKD, especially with albuminuria) or heart failure; a description of the safety of SGLT2is, with a special focus on the risk/benefit balance in people with stage 3 CKD; a comprehensive discussion of mechanisms that could explain nephro-protection; a reappraisal of the positioning of SGLT2is in recent international guidelines. EXPERT OPINION Several mechanisms could contribute to improved renal prognosis with SGLT2is, among which a reduction in intraglomerular pressure by restoring the tubuloglomerular feedback, a diuretic effect that contributes to lower albuminuria and renal decongestion, especially if fluid overload is present, a reduction in renal oxygen consumption, an improvement of heart failure status with less cardiorenal syndrome and a lower risk of acute renal injury. All these effects may be mutually not exclusive, and their respective contribution may differ according to patient characteristics.
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Affiliation(s)
- André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium
- Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège (ULiege), Liège, Belgium
| | - Pierre Delanaye
- Department of Nephrology-Dialysis-Transplantation, University of Liège (ULiege), CHU Sart Tilman, Liège, Belgium
- Department of Nephrology-Dialysis-Apheresis, Hôpital Universitaire Carémeau, Nîmes, France
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21
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Ujjawal A, Schreiber B, Verma A. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) in kidney transplant recipients: what is the evidence? Ther Adv Endocrinol Metab 2022; 13:20420188221090001. [PMID: 35450095 PMCID: PMC9016587 DOI: 10.1177/20420188221090001] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 03/04/2022] [Indexed: 12/15/2022] Open
Abstract
Several recent randomized controlled trials (RCTs) have demonstrated the wide clinical application of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in improving kidney and cardiovascular outcomes in patients with native kidney disease. In April 2021, Dapagliflozin became the first SGLT2 inhibitor to be approved by the Food and Drug Administration (FDA) for the treatment of chronic kidney disease (CKD) regardless of diabetic status. However, while these agents have drawn much acclaim for their cardiovascular and nephroprotective effects among patients with native kidney disease, little is known about the safety and efficacy of SGLT2i in the kidney transplant setting. Many of the mechanisms by which SGLT2i exert their benefit stand to prove equally as efficacious or more so among kidney transplant recipients as they have in patients with CKD. However, safety concerns have excluded transplant recipients from all large RCTs, and clinicians and patients alike are left to wonder if the benefits of these amazing drugs outweigh the risks. In this review, we will discuss the known mechanisms SGLT2i exploit to provide their beneficial effects, the potential benefits, and risks of these agents in the context of kidney transplantation, and finally, we will discuss current findings of the published literature for SGLT2i use in kidney transplant recipients and propose potential directions for future research.
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22
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Delanaye P, Scheen AJ. The diuretic effects of SGLT2 inhibitors: A comprehensive review of their specificities and their role in renal protection. DIABETES & METABOLISM 2021; 47:101285. [PMID: 34597788 DOI: 10.1016/j.diabet.2021.101285] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 09/16/2021] [Indexed: 02/08/2023]
Abstract
Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are new oral glucose-lowering agents that provide cardiovascular and renal protection in both patients with and without type 2 diabetes. Because of their unique mechanism of action, increased glucosuria is associated with osmotic diuresis and some natriuresis, yet the latter seems mostly transient. The potential role of the diuretic effect in overall cardiovascular and renal protection by SGLT2is remains a matter of debate. Precise evaluation of the diuretic effect is not so easy and most studies relied upon indirect estimations that led to divergent results, presumably also explained by different study designs and population characteristics. Everybody agrees upon the fact that SGLT2is are different from other classical diuretics (thiazides and loop diuretics) as they present some favourable properties, i.e. reduced sympathetic activity, preserved potassium balance, lower risk of acute renal injury, decrease of serum uric acid level. The potential role of the diuretic effect of SGLT2is on renal outcomes is still unclear, yet their ability to reduce albuminuria and dampen the risk of heart failure may contribute to improve renal prognosis besides other complex underlying mechanisms. In this comprehensive review we first critically analyse the results obtained with indirect methods that assess a diuretic effect of SGLT2is, second we describe the specificities of the diuretic activity of SGLT2is compared with other classical diuretics, and third we discuss the potential mechanisms by which the diuretic effect of SGLT2is could contribute to the improvement of renal outcomes consistently reported with this innovative amazing pharmacological class.
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Affiliation(s)
- Pierre Delanaye
- Department of Nephrology-Dialysis-Transplantation, University of Liège (ULg CHU), CHU Sart Tilman, Liège, Belgium; Department of Nephrology-Dialysis-Apheresis, Hôpital Universitaire Carémeau, Nimes, France
| | - Andre J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium; Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium.
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23
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Gitto M, Vrachatis DA, Condorelli G, Papathanasiou K, Reimers B, Deftereos S, Stefanini GG. Potential Therapeutic Benefits of Sodium-Glucose Cotransporter 2 Inhibitors in the Context of Ischemic Heart Failure: A State-Of-The-Art Review. Cardiovasc Hematol Agents Med Chem 2021; 20:90-102. [PMID: 34370645 DOI: 10.2174/1871525719666210809121016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/25/2021] [Accepted: 07/15/2021] [Indexed: 11/22/2022]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of anti-diabetic agents that block the reabsorption of glucose in the proximal convoluted tubule of the nephron, thereby contributing to glycosuria and lowering blood glucose levels. SGLT2 inhibitors have been associated with improved cardiovascular outcomes in patients with diabetes, including a reduced risk of cardiovascular death and hospitalizations for heart failure. Recently, DAPA-HF and EMPEROR REDUCED trials showed the beneficial cardiovascular effect of SGLT2 inhibitors in patients with heart failure with consistently reduced ejection fraction (HFrEF) regardless of the presence of diabetes. Moreover, some exploratory studies suggested that these drugs improve Left Ventricular (LV) systolic function and oppose LV adverse remodeling in patients with HFrEF. However, the exact mechanisms that mediated for this benefit are not fully understood. Beyond glycemic control, enhanced natriuresis, increased erythropoiesis, improved endothelial function, changes in myocardial metabolism, anti-inflammatory and anti-oxidative properties may all play an active role in SGLT2 inhibitors' cardiovascular benefits. A deep understanding of the pathophysiological interplay is key to define which HF phenotype could benefit more from SGLT2 inhibitors. Current clinical evidence on the comparison of different HF etiologies is limited to posthoc subgroup analysis of DAPA-HF and EMPEROR-REDUCED, which showed similar outcomes in patients with or without ischemic HF. On the other hand, in earlier studies of patients suffering from diabetes, rates of classic ischemic endpoints, such as myocardial infarction, stroke or coronary revascularization, did not differ between patients treated with SGLT2 inhibitors or placebo. The aim of this review is to discuss whether SGLT2 inhibitors may improve prognosis in patients with ischemic HF, not only in terms of reducing re-hospitalizations and improving left ventricular function but also by limiting coronary artery disease progression and ischemic burden.
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Affiliation(s)
- Mauro Gitto
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy
| | - Dimitrios A Vrachatis
- 2nd Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece
| | - Gianluigi Condorelli
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy
| | | | - Bernhard Reimers
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy
| | - Spyridon Deftereos
- 2nd Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece
| | - Giulio G Stefanini
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy
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24
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Goldberg LR. The Pleiotropic Effects of SGLT2 Inhibitors: Remodeling the Treatment of Heart Failure. J Am Coll Cardiol 2021; 77:256-258. [PMID: 33478648 DOI: 10.1016/j.jacc.2020.11.029] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 11/17/2020] [Indexed: 10/22/2022]
Affiliation(s)
- Lee R Goldberg
- Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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25
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Albiero M, Tedesco S, Amendolagine FI, D'Anna M, Migliozzi L, Zuccolotto G, Rosato A, Cappellari R, Avogaro A, Fadini GP. Inhibition of SGLT2 Rescues Bone Marrow Cell Traffic for Vascular Repair: Role of Glucose Control and Ketogenesis. Diabetes 2021; 70:1767-1779. [PMID: 33903150 DOI: 10.2337/db20-1045] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 04/21/2021] [Indexed: 11/13/2022]
Abstract
The mechanisms by which sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve cardiovascular outcomes in people with diabetes are incompletely understood. Recent studies show that SGLT2i may increase the levels of circulating cells with vascular regenerative capacity, at least in part by lowering glycemia. In this study, we used mice with streptozotocin-induced diabetes treated with the SGLT2i dapagliflozin at a dose that reduced glucose levels by 20%. Dapagliflozin improved the diabetes-associated defect of hematopoietic stem cell mobilization after stimulation with granulocyte colony-stimulating factor. Dapagliflozin rescued the traffic of bone marrow (BM)-derived cells to injured carotid arteries and improved endothelial healing in diabetic mice. Defective homing of CD49d+ granulocytes was causally linked with impaired endothelial repair and was reversed by dapagliflozin. The effects of dapagliflozin were mimicked by a similar extent of glucose reduction achieved with insulin therapy and by a ketone drink that artificially elevated β-hydroxybutyrate. Inhibition of endothelial repair by resident cells using the CXCR4 antagonist AMD3100 did not abolish the vascular effect of dapagliflozin, indirectly supporting that endothelial healing by dapagliflozin was mediated by recruitment of circulating cells. In summary, we show that dapagliflozin improved the traffic of BM-derived hematopoietic cells to the site of vascular injury, providing a hitherto unappreciated mechanism of vascular protection.
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Affiliation(s)
- Mattia Albiero
- Department of Medicine, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | - Serena Tedesco
- Department of Medicine, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | | | - Marianna D'Anna
- Department of Medicine, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | - Ludovica Migliozzi
- Department of Medicine, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | - Gaia Zuccolotto
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Istituto Oncologico Veneto-Istituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy
| | - Antonio Rosato
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
- Istituto Oncologico Veneto-Istituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy
| | - Roberta Cappellari
- Department of Medicine, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | - Angelo Avogaro
- Department of Medicine, University of Padova, Padova, Italy
| | - Gian Paolo Fadini
- Department of Medicine, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
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26
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Kreutzer FP, Meinecke A, Schmidt K, Fiedler J, Thum T. Alternative strategies in cardiac preclinical research and new clinical trial formats. Cardiovasc Res 2021; 118:746-762. [PMID: 33693475 PMCID: PMC7989574 DOI: 10.1093/cvr/cvab075] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 03/03/2021] [Indexed: 02/07/2023] Open
Abstract
An efficient and safe drug development process is crucial for the establishment of new drugs on the market aiming to increase quality of life and life-span of our patients. Despite technological advances in the past decade, successful launches of drug candidates per year remain low. We here give an overview about some of these advances and suggest improvements for implementation to boost preclinical and clinical drug development with a focus on the cardiovascular field. We highlight advantages and disadvantages of animal experimentation and thoroughly review alternatives in the field of three-dimensional cell culture as well as preclinical use of spheroids and organoids. Microfluidic devices and their potential as organ-on-a-chip systems, as well as the use of living animal and human cardiac tissues are additionally introduced. In the second part, we examine recent gold standard randomized clinical trials and present possible modifications to increase lead candidate throughput: adaptive designs, master protocols, and drug repurposing. In silico and N-of-1 trials have the potential to redefine clinical drug candidate evaluation. Finally, we briefly discuss clinical trial designs during pandemic times.
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Affiliation(s)
- Fabian Philipp Kreutzer
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Anna Meinecke
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Kevin Schmidt
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Jan Fiedler
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.,REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany.,Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.,REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany.,Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany
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27
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Zhou H, Ren J, Toan S, Mui D. Role of mitochondrial quality surveillance in myocardial infarction: From bench to bedside. Ageing Res Rev 2021; 66:101250. [PMID: 33388396 DOI: 10.1016/j.arr.2020.101250] [Citation(s) in RCA: 168] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 12/10/2020] [Accepted: 12/22/2020] [Indexed: 12/17/2022]
Abstract
Myocardial infarction (MI) is the irreversible death of cardiomyocyte secondary to prolonged lack of oxygen or fresh blood supply. Historically considered as merely cardiomyocyte powerhouse that manufactures ATP and other metabolites, mitochondrion is recently being identified as a signal regulator that is implicated in the crosstalk and signal integration of cardiomyocyte contraction, metabolism, inflammation, and death. Mitochondria quality surveillance is an integrated network system modifying mitochondrial structure and function through the coordination of various processes including mitochondrial fission, fusion, biogenesis, bioenergetics, proteostasis, and degradation via mitophagy. Mitochondrial fission favors the elimination of depolarized mitochondria through mitophagy, whereas mitochondrial fusion preserves the mitochondrial network upon stress through integration of two or more small mitochondria into an interconnected phenotype. Mitochondrial biogenesis represents a regenerative program to replace old and damaged mitochondria with new and healthy ones. Mitochondrial bioenergetics is regulated by a metabolic switch between glucose and fatty acid usage, depending on oxygen availability. To maintain the diversity and function of mitochondrial proteins, a specialized protein quality control machinery regulates protein dynamics and function through the activity of chaperones and proteases, and induction of the mitochondrial unfolded protein response. In this review, we provide an overview of the molecular mechanisms governing mitochondrial quality surveillance and highlight the most recent preclinical and clinical therapeutic approaches to restore mitochondrial fitness during both MI and post-MI heart failure.
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Affiliation(s)
- Hao Zhou
- Department of Cardiology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing 100853, China.
| | - Jun Ren
- Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA
| | - Sam Toan
- Department of Chemical Engineering, University of Minnesota-Duluth, Duluth, MN 55812, USA
| | - David Mui
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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28
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Shaffner J, Chen B, Malhotra DK, Dworkin LD, Gong R. Therapeutic Targeting of SGLT2: A New Era in the Treatment of Diabetes and Diabetic Kidney Disease. Front Endocrinol (Lausanne) 2021; 12:749010. [PMID: 34790170 PMCID: PMC8591164 DOI: 10.3389/fendo.2021.749010] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 10/14/2021] [Indexed: 12/20/2022] Open
Abstract
As the prevalence of diabetic kidney disease (DKD) continues to rise, so does the need for a novel therapeutic modality that can control and slow its progression to end-stage renal disease. The advent of sodium-glucose cotransporter-2 (SGLT2) inhibitors has provided a major advancement for the treatment of DKD. However, there still remains insufficient understanding of the mechanism of action and effectiveness of this drug, and as a result, its use has been very limited. Burgeoning evidence suggests that the SGLT2 inhibitors possess renal protective activities that are able to lower glycemic levels, improve blood pressure/hemodynamics, cause bodyweight loss, mitigate oxidative stress, exert anti-inflammatory and anti-fibrotic effects, reduce urinary albumin excretion, lower uric acid levels, diminish the activity of intrarenal renin-angiotensin-aldosterone system, and reduce natriuretic peptide levels. SGLT2 inhibitors have been shown to be safe and beneficial for use in patients with a GFR ≥30mL/min/1.73m2, associated with a constellation of signs of metabolic reprogramming, including enhanced ketogenesis, which may be responsible for the correction of metabolic reprogramming that underlies DKD. This article aims to provide a comprehensive overview and better understanding of the SGLT2 inhibitor and its benefits as it pertains to renal pathophysiology. It summarizes our recent understanding on the mechanisms of action of SGLT2 inhibitors, discusses the effects of SGLT2 inhibitors on diabetes and DKD, and presents future research directions and therapeutic potential.
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