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Yoo TT, Baek IH, Stoletniy L, Hilliard A, Sakr A, Doycheva D. Impact of sodium-glucose transport protein-2 (SGLT2) inhibitors on the inflammasome pathway in acute myocardial infarction in type 2 diabetes mellitus: a comprehensive review. Cardiovasc Diabetol 2025; 24:227. [PMID: 40420176 PMCID: PMC12105141 DOI: 10.1186/s12933-025-02777-7] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Accepted: 05/06/2025] [Indexed: 05/28/2025] Open
Abstract
Sodium-glucose transport protein-2 (SGLT2) inhibitors, initially developed for glycemic control in type 2 diabetes mellitus (T2DM), have emerged as potential cardioprotective agents, reducing cardiovascular mortality and improving heart failure outcomes. Recent evidence suggests that SGLT2 inhibitors exert anti-inflammatory effects, particularly through modulating the inflammasome pathway. This review explores the role of the inflammasome in acute myocardial infarction (AMI) in T2DM and discusses the mechanisms by which SGLT2 inhibitors influence this pathway. We evaluate current studies on the impact of SGLT2 inhibitors on key inflammatory mediators, particularly the NLRP3 inflammasome, and discuss their potential therapeutic implications for reducing inflammation and myocardial injury in patients with T2DM experiencing AMI. In summary, the key novelties in this review lie in its focused mechanistic approach on the inflammasome pathway, its integration of diabetes and cardiovascular research, and its potential to influence future therapeutic strategies for AMI in T2DM patients. It offers a novel angle by tying together molecular mechanisms of inflammation with clinical implications in a specific patient population that faces high cardiovascular risk.
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Affiliation(s)
- Thomas T Yoo
- Department of Internal Medicine, Loma Linda University Medical Center, Loma Linda, CA, 92354, USA
| | - In Hae Baek
- Department of Internal Medicine, Loma Linda University Medical Center, Loma Linda, CA, 92354, USA
| | - Liset Stoletniy
- Division of Cardiology, School of Medicine, Loma Linda University, 11234 Anderson St, Loma Linda, CA, 92354, USA
- Department of Internal Medicine, Loma Linda University Medical Center, Loma Linda, CA, 92354, USA
| | - Anthony Hilliard
- Division of Cardiology, School of Medicine, Loma Linda University, 11234 Anderson St, Loma Linda, CA, 92354, USA
- Department of Internal Medicine, Loma Linda University Medical Center, Loma Linda, CA, 92354, USA
| | - Antoine Sakr
- Division of Cardiology, School of Medicine, Loma Linda University, 11234 Anderson St, Loma Linda, CA, 92354, USA
- Department of Internal Medicine, Loma Linda University Medical Center, Loma Linda, CA, 92354, USA
| | - Desislava Doycheva
- Division of Cardiology, School of Medicine, Loma Linda University, 11234 Anderson St, Loma Linda, CA, 92354, USA.
- Department of Physiology and Pharmacology, Loma Linda University, 11175 Campus St, Loma Linda, CA, 92354, USA.
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Ivey-Miranda JB, Rao VS, Cox ZL, Moreno-Villagomez J, Ramos Mastache D, Collins SP, Testani JM. Natriuretic response prediction equation for use with oral diuretics in heart failure. Eur Heart J 2025:ehaf268. [PMID: 40272149 DOI: 10.1093/eurheartj/ehaf268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 11/15/2024] [Accepted: 03/31/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND AND AIMS Limited data are available to assess oral diuretic response in outpatients with heart failure (HF). The natriuretic response prediction equation (NRPE) predicts natriuresis following a loop diuretic dose using a urine sample 2 h after the dose and was validated to accurately predict intravenous diuretic response. The primary aim was to validate the NRPE's assessment of oral diuretic response in patients with HF. METHODS The NRPE was evaluated in two HF patient cohorts receiving oral loop diuretics: Mechanisms of Diuretic Resistance (MDR) and TRANSFORM-Mechanism. Participants received their home oral loop diuretic followed by a supervised timed urine collection including spot urine samples at 1 and 2 h. Patients quantified their self-assessed diuretic response (urine volume) via a standardized survey. A poor diuretic response was defined as cumulative natriuresis < 50 mmol over the study visit. RESULTS The MDR cohort included 318 oral diuretic administrations from 237 patients. The NRPE predicted a poor natriuretic response with an area under the curve (AUC) of .87 [95% confidence interval (CI) .83-.91] and similar accuracy to the previously validated intravenous NRPE performance (P = .16). Patient's ability to self-estimate their diuretic response was poor with an AUC of .57 (95% CI .44-.70) and significantly worse than the oral NRPE (P < .001). In TRANSFORM-Mechanism (110 oral diuretic administrations), the NRPE had similar operating characteristics (AUC .89, 95% CI .80-1.0) for poor diuretic response. CONCLUSIONS Natriuretic response to an oral diuretic can be rapidly and accurately assessed with a urine sample collected 2 h after an oral diuretic dose and the NRPE.
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Affiliation(s)
- Juan B Ivey-Miranda
- Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, USA
- Department of Heart Failure, Hospital de Cardiologia, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Veena S Rao
- Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, USA
| | - Zachary L Cox
- Department of Pharmacy Practice, Lipscomb University College of Pharmacy, Nashville, TN, USA
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Julieta Moreno-Villagomez
- Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Daniela Ramos Mastache
- Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Sean P Collins
- Deparment of Emergency Medicine, Vanderbilt University Medical Center, Geriatric Research and Education Clinical Care, Tennessee Valley Healthcare Facility VA Medical Center, Nashville, TN, USA
| | - Jeffrey M Testani
- Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, USA
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Zhang JJ, Ye XR, Liu XS, Zhang HL, Qiao Q. Impact of sodium-glucose cotransporter-2 inhibitors on pulmonary vascular cell function and arterial remodeling. World J Cardiol 2025; 17:101491. [PMID: 39866213 PMCID: PMC11755123 DOI: 10.4330/wjc.v17.i1.101491] [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: 09/19/2024] [Revised: 11/02/2024] [Accepted: 12/17/2024] [Indexed: 01/21/2025] Open
Abstract
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors represent a cutting-edge class of oral antidiabetic therapeutics that operate through selective inhibition of glucose reabsorption in proximal renal tubules, consequently augmenting urinary glucose excretion and attenuating blood glucose levels. Extensive clinical investigations have demonstrated their profound cardiovascular efficacy. Parallel basic science research has elucidated the mechanistic pathways through which diverse SGLT-2 inhibitors beneficially modulate pulmonary vascular cells and arterial remodeling. Specifically, these inhibitors exhibit promising potential in enhancing pulmonary vascular endothelial cell function, suppressing pulmonary smooth muscle cell proliferation and migration, reversing pulmonary arterial remodeling, and maintaining hemodynamic equilibrium. This comprehensive review synthesizes current literature to delineate the mechanisms by which SGLT-2 inhibitors enhance pulmonary vascular cell function and reverse pulmonary remodeling, thereby offering novel therapeutic perspectives for pulmonary vascular diseases.
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Affiliation(s)
- Jing-Jing Zhang
- Chinese Academy Medical Sciences, Fuwai Yunnan Hospital, Kunming 650000, Yunnan Province, China
- Kunming Medical University, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming 650000, Yunnan Province, China
| | - Xue-Rui Ye
- Chinese Academy Medical Sciences, Fuwai Yunnan Hospital, Kunming 650000, Yunnan Province, China
- Kunming Medical University, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming 650000, Yunnan Province, China
| | - Xue-Song Liu
- Department of Biochemistry, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hao-Ling Zhang
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Qian Qiao
- Chinese Academy Medical Sciences, Fuwai Yunnan Hospital, Kunming 650000, Yunnan Province, China
- Kunming Medical University, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming 650000, Yunnan Province, China.
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Bak M, Chi SA, Jeon K, Hong D, Shin H, Kim D, Choi JO. Discontinuation rates, clinical effects and provocation factors of SGLT-2 inhibitor in the real world. Sci Rep 2024; 14:30653. [PMID: 39730335 DOI: 10.1038/s41598-024-71231-7] [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: 03/14/2024] [Accepted: 08/26/2024] [Indexed: 12/29/2024] Open
Abstract
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are the only medications that improve clinical outcomes regardless of baseline left ventricular ejection fraction. Despite the recognized effectiveness of SGLT-2 inhibitors, there remains a paucity of research on the discontinuation of these medications. The objective of this study is to analyze the rate of discontinuation of SGLT-2 inhibitors, to evaluate the impact of discontinuation on the clinical outcome, and to identify the factors associated with discontinuation. From 2015 to 2021, 775 heart failure patients prescribed an SGLT-2 inhibitor were retrospectively collated at Samsung Medical Center, Seoul, Republic of Korea. The SGLT-2 inhibitor discontinuation rate and the effect of SGLT-2 inhibitor discontinuation on clinical outcome were analyzed using the Kaplan-Meier survival curve. Factors related to discontinuation were analyzed through Cox regression and competing risk survival analysis. The discontinuation rate of SGLT-2 inhibitors was 7.5% at 1 year and 20% at 5 years. General weakness, over-diuresis and volume depletion, renal dysfunction progression, and urinary tract infections are the major reasons for discontinuing SGLT-2 inhibitors in general medical practice. The group that stopped using SGLT-2 inhibitors had a higher rate of heart failure hospitalization than the control group (adjusted HR 2.600, 95% CI [1.233-5.481], P = 0.012). In multivariable Cox regression analysis, the factors associated with total SGLT-2 inhibitor discontinuation were women (HR 2.478, 95% CI [1.553-3.953], P < 0.001) and lower estimated glomerular filtration rate (eGFR) (HR 0.884 per 10 ml/min/1.73 m2, 95% CI [0.789-0.991], P = 0.034). Patients who discontinued SGLT-2 inhibitors experienced an increased risk of heart failure hospitalization, and the rate of discontinuation was higher in women and those with lower eGFR.
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Affiliation(s)
- Minjung Bak
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sang Ah Chi
- Biomedical Statistics Center, Data Science Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Kina Jeon
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Division of Cardiology, Department of Internal Medicine, Konkuk University School of Medicine, Konkuk University Medical Center, Seoul, Korea
| | - David Hong
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Heayoung Shin
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Darae Kim
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jin-Oh Choi
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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Brata R, Pascalau AV, Fratila O, Paul I, Muresan MM, Camarasan A, Ilias T. Hemodynamic Effects of SGLT2 Inhibitors in Patients with and Without Diabetes Mellitus-A Narrative Review. Healthcare (Basel) 2024; 12:2464. [PMID: 39685086 DOI: 10.3390/healthcare12232464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 12/01/2024] [Accepted: 12/04/2024] [Indexed: 12/18/2024] Open
Abstract
Background: The current review aims to present the beneficial effects of SGLT2 inhibitors (dapagliflozin and empagliflozin) on several hemodynamic parameters such as blood pressure, filtration pressure at the level of the glomerular capillaries, and the improvement of the preload and afterload of heart muscle. In order to stop chronic kidney disease (CKD) from progressing, SGLT2 inhibitors have become an important disease-modifying treatment. Materials and methods: Recent clinical studies have shown the success of these drugs in treating heart failure, reducing the risk of cardiovascular events, hospitalization, and mortality. Results: The hemodynamic effects of SGLT2 inhibitors include a diuretic effect, due to reduced sodium reabsorption. Also, at this level, numerous studies have confirmed the beneficial effect of dapagliflozin in patients with chronic kidney disease, associated with a 44% reduced risk of progression in this pathology. SGLT2 inhibitors are associated with a reduction in blood pressure and weight loss, because of their diuretic effect, especially empagliflozin, which can explain the beneficial effects in patients with heart failure. In addition, mainly empagliflozin reduces stiffness and arterial resistance. Conclusions: Although the exact mechanism of action is unknown, SGLT2 inhibitors reduce the interstitial volume by blocking the tubular reabsorption of glucose. This leads to reduced blood pressure and enhanced endothelial function. Consequently, there have been improvements in hospitalization and fatality rates. Because of their beneficial effects, these medications have been guidelines for managing heart failure and chronic kidney disease.
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Affiliation(s)
- Roxana Brata
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 December 10, 410073 Oradea, Romania
| | - Andrei Vasile Pascalau
- Department of Morphological Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 December 10, 410073 Oradea, Romania
| | - Ovidiu Fratila
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 December 10, 410073 Oradea, Romania
| | - Ioana Paul
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 December 10, 410073 Oradea, Romania
| | - Mihaela Mirela Muresan
- Department of Morphological Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 December 10, 410073 Oradea, Romania
| | - Andreea Camarasan
- Department of Morphological Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 December 10, 410073 Oradea, Romania
| | - Tiberia Ilias
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 December 10, 410073 Oradea, Romania
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Vallon V. State-of-the-Art-Review: Mechanisms of Action of SGLT2 Inhibitors and Clinical Implications. Am J Hypertens 2024; 37:841-852. [PMID: 39017631 PMCID: PMC11471837 DOI: 10.1093/ajh/hpae092] [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: 07/11/2024] [Revised: 07/12/2024] [Accepted: 07/13/2024] [Indexed: 07/18/2024] Open
Abstract
BACKGROUND Inhibitors of the Na+-coupled glucose transporter SGLT2 (SGLT2i) primarily shift the reabsorption of large amounts of glucose from the kidney's early proximal tubule to downstream tubular segments expressing SGLT1, and the non-reabsorbed glucose is spilled into the urine together with some osmotic diuresis. How can this protect the kidneys and heart from failing as observed in individuals with and without type 2 diabetes? GOAL Mediation analyses identified clinical phenotypes of SGLT2i associated with improved kidney and heart outcome, including a reduction of plasma volume or increase in hematocrit, and lowering of serum urate levels and albuminuria. This review outlines how primary effects of SGLT2i on the early proximal tubule can explain these phenotypes. RESULTS The physiology of tubule-glomerular communication provides the basis for acute lowering of GFR and glomerular capillary pressure, which contributes to lowering of albuminuria but also to long term preservation of GFR, at least in part by reducing kidney cortex oxygen demand. Functional co-regulation of SGLT2 with other sodium and metabolite transporters in the early proximal tubule explains why SGLT2i initially excrete more sodium than expected and are uricosuric, thereby reducing plasma volume and serum urate. Inhibition of SGLT2 reduces early proximal tubule gluco-toxicity and by shifting transport downstream may simulate "systemic hypoxia", and the resulting increase in erythropoiesis, together with the osmotic diuresis, enhances hematocrit and improves blood oxygen delivery. Cardio-renal protection by SGLT2i is also provided by a fasting-like and insulin-sparing metabolic phenotype and, potentially, by off-target effects on the heart and microbiotic formation of uremic toxins.
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Affiliation(s)
- Volker Vallon
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, La Jolla, California, USA
- Department of Pharmacology, University of California San Diego, La Jolla, California, USA
- VA San Diego Healthcare System, San Diego, California, USA
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7
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Vallon V. How can inhibition of glucose and sodium transport in the early proximal tubule protect the cardiorenal system? Nephrol Dial Transplant 2024; 39:1565-1573. [PMID: 38439675 PMCID: PMC11427065 DOI: 10.1093/ndt/gfae060] [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: 02/04/2024] [Indexed: 03/06/2024] Open
Abstract
What mechanisms can link the inhibition of sodium-glucose cotransporter 2 (SGLT2) in the early proximal tubule to kidney and heart protection in patients with and without type 2 diabetes? Due to physical and functional coupling of SGLT2 to other sodium and metabolite transporters in the early proximal tubule (including NHE3, URAT1), inhibitors of SGLT2 (SGLT2i) reduce reabsorption not only of glucose, inducing osmotic diuresis, but of other metabolites plus of a larger amount of sodium than expected based on SGLT2 inhibition alone, thereby reducing volume retention, hypertension and hyperuricemia. Metabolic adaptations to SGLT2i include a fasting-like response, with enhanced lipolysis and formation of ketone bodies that serve as additional fuel for kidneys and heart. Making use of the physiology of tubulo-glomerular communication, SGLT2i functionally lower glomerular capillary pressure and filtration rate, thereby reducing physical stress on the glomerular filtration barrier, tubular exposure to albumin and nephrotoxic compounds, and the oxygen demand for reabsorbing the filtered load. Together with reduced gluco-toxicity in the early proximal tubule and better distribution of transport work along the nephron, SGLT2i can preserve tubular integrity and transport function and, thereby, glomerular filtration rate in the long-term. By shifting transport downstream, SGLT2i may simulate systemic hypoxia at the oxygen sensors in the deep cortex/outer medulla, which stimulates erythropoiesis and, together with osmotic diuresis, enhances hematocrit and thereby improves oxygen delivery to all organs. The described SGLT2-dependent effects may be complemented by off-target effects of SGLT2i on the heart itself and on the microbiome formation of cardiovascular-effective uremic toxins.
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Affiliation(s)
- Volker Vallon
- Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
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Girardi ACC, Polidoro JZ, Castro PC, Pio-Abreu A, Noronha IL, Drager LF. Mechanisms of heart failure and chronic kidney disease protection by SGLT2 inhibitors in nondiabetic conditions. Am J Physiol Cell Physiol 2024; 327:C525-C544. [PMID: 38881421 DOI: 10.1152/ajpcell.00143.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 06/11/2024] [Accepted: 06/11/2024] [Indexed: 06/18/2024]
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2is), initially developed for type 2 diabetes (T2D) treatment, have demonstrated significant cardiovascular and renal benefits in heart failure (HF) and chronic kidney disease (CKD), irrespective of T2D. This review provides an analysis of the multifaceted mechanisms underlying the cardiorenal benefits of SGLT2i in HF and CKD outside of the T2D context. Eight major aspects of the protective effects of SGLT2i beyond glycemic control are explored: 1) the impact on renal hemodynamics and tubuloglomerular feedback; 2) the natriuretic effects via proximal tubule Na+/H+ exchanger NHE3 inhibition; 3) the modulation of neurohumoral pathways with evidence of attenuated sympathetic activity; 4) the impact on erythropoiesis, not only in the context of local hypoxia but also systemic inflammation and iron regulation; 5) the uricosuria and mitigation of the hyperuricemic environment in cardiorenal syndromes; 6) the multiorgan metabolic reprogramming including the potential induction of a fasting-like state, improvement in glucose and insulin tolerance, and stimulation of lipolysis and ketogenesis; 7) the vascular endothelial growth factor A (VEGF-A) upregulation and angiogenesis, and 8) the direct cardiac effects. The intricate interplay between renal, neurohumoral, metabolic, and cardiac effects underscores the complexity of SGLT2i actions and provides valuable insights into their therapeutic implications for HF and CKD. Furthermore, this review sets the stage for future research to evaluate the individual contributions of these mechanisms in diverse clinical settings.
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Affiliation(s)
- Adriana C C Girardi
- Laboratório de Genética e Cardiologia Molecular, Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Juliano Z Polidoro
- Laboratório de Genética e Cardiologia Molecular, Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Paulo C Castro
- Laboratório de Genética e Cardiologia Molecular, Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Andrea Pio-Abreu
- Disciplina de Nefrologia, Faculdade de Medicina, Hospital das Clínicas HCFMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Irene L Noronha
- Disciplina de Nefrologia, Faculdade de Medicina, Hospital das Clínicas HCFMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Luciano F Drager
- Disciplina de Nefrologia, Faculdade de Medicina, Hospital das Clínicas HCFMUSP, Universidade de São Paulo, São Paulo, Brazil
- Unidade de Hipertensão, Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, São Paulo, Brazil
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Buttar C, Alai H, Matanes FN, Cassidy MM, Stencel J, Le Jemtel TH. Full decongestion in acute heart failure therapy. Am J Med Sci 2024; 368:182-189. [PMID: 38880301 DOI: 10.1016/j.amjms.2024.06.002] [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: 03/24/2024] [Revised: 06/07/2024] [Accepted: 06/07/2024] [Indexed: 06/18/2024]
Abstract
Incomplete decongestion is the main cause of readmission in the early post-discharge period of a hospitalization for acute heart failure. Recent heart failure guidelines have highlighted initiation and rapid up-titration of quadruple therapy with angiotensin receptor neprilysin inhibitor, beta adrenergic receptor blocker, mineralocorticoid receptor antagonist, and sodium glucose cotransporter 2 inhibitor to prevent hospitalizations for heart failure with reduced ejection fraction. However, full decongestion remains the foremost therapeutic goal of hospitalization for heart failure. While early addition of sodium glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists may be helpful, the value of the other therapeutics comes after decongestion is complete.
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Affiliation(s)
- Chandan Buttar
- Department of Cardiology, Tulane University Medical Center, 1415 Tulane Ave, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Healthcare System, 2400 Canal Street, New Orleans, LA 70119, USA
| | - Hamid Alai
- Department of Cardiology, Tulane University Medical Center, 1415 Tulane Ave, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Healthcare System, 2400 Canal Street, New Orleans, LA 70119, USA
| | - Faris N Matanes
- Department of Cardiology, Tulane University Medical Center, 1415 Tulane Ave, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Healthcare System, 2400 Canal Street, New Orleans, LA 70119, USA
| | - Mark M Cassidy
- Department of Cardiology, Tulane University Medical Center, 1415 Tulane Ave, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Healthcare System, 2400 Canal Street, New Orleans, LA 70119, USA
| | - Jason Stencel
- Department of Cardiology, Tulane University Medical Center, 1415 Tulane Ave, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Healthcare System, 2400 Canal Street, New Orleans, LA 70119, USA
| | - Thierry H Le Jemtel
- Department of Cardiology, Tulane University Medical Center, 1415 Tulane Ave, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Healthcare System, 2400 Canal Street, New Orleans, LA 70119, USA.
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Fardman A, Kodesh A, Siegel AJ, Segev A, Regev E, Maor E, Berkovitch A, Kuperstein R, Morgan A, Nahum E, Peled Y, Grupper A. The safety of sodium glucose transporter 2 inhibitors and trends in clinical and hemodynamic parameters in patients with left ventricular assist devices. Artif Organs 2024; 48:902-911. [PMID: 38409872 DOI: 10.1111/aor.14733] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 12/14/2023] [Accepted: 02/12/2024] [Indexed: 02/28/2024]
Abstract
BACKGROUND The safety and impact of sodium glucose transporter 2 inhibitors (SGLT2-I) in patients with left ventricular assist devices (LVAD) are unknown. METHODS A retrospective analysis of all consecutive patients who underwent LVAD Heart Mate 3 (HM3) implantation at a single medical center and received SGLT2-I therapy following surgery was conducted. LVAD parameters, medical therapy, laboratory tests, echocardiography, and right heart catheterization (RHC) study results were recorded and compared before and after initiation of SGLT2-I. RESULTS SGLT2-I medications were initiated in 29 (21%) of 138 patients following HM3 implantation (23 (79%) received Empagliflozin and 6 (21%) Dapagliflozin). The mean age at the time of LVAD implantation was 62 ± 6.7 years, 25 (86%) were male, and 23 (79%) had diabetes mellitus. The median time from HM3 implantation to SGLT2-I initiation was 108 days, IQR (26-477). Following SGLT2-I therapy, the daily dose of furosemide decreased from 47 to 23.5 mg/day (mean difference = 23.5 mg/d, 95% CI 8.2-38.7, p = 0.004) and significant weight reduction was observed (mean difference 2.5 kg, 95% CI 0.7-4.3, p = 0.008). Moreover, a significant 5.6 mm Hg reduction in systolic pulmonary artery pressure (sPAP) was measured during RHC (95% CI 0.23-11, p = 0.042) in a subgroup of 11 (38%) patients. LVAD parameters were similar before and after SGLT2-I initiation (p > 0.2 for all). No adverse events were recorded during median follow-up of 354 days, IQR (206-786). CONCLUSION SGLT2-I treatment is safe in LVAD patients and might contribute to reduction in patients sPAP.
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Affiliation(s)
- Alexander Fardman
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Afek Kodesh
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
- Department of Internal Medicine, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, USA
| | | | - Amitai Segev
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Ehud Regev
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Elad Maor
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Anat Berkovitch
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Rafael Kuperstein
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Avi Morgan
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Eyal Nahum
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Yael Peled
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Avishay Grupper
- The Cardiovascular Division, Sheba Medical Center, Tel Hashomer, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
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11
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Castro PC, Santos-Rios TM, Martins FL, Crajoinas RO, Caetano MV, Lessa LMA, Luchi WM, McCormick JA, Girardi ACC. Renal upregulation of NCC counteracts empagliflozin-mediated NHE3 inhibition in normotensive but not in hypertensive male rat. Am J Physiol Cell Physiol 2024; 326:C1573-C1589. [PMID: 38557357 PMCID: PMC11932537 DOI: 10.1152/ajpcell.00351.2023] [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: 07/31/2023] [Revised: 03/21/2024] [Accepted: 03/21/2024] [Indexed: 04/04/2024]
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce blood pressure (BP) in patients with hypertension, yet the precise molecular mechanisms remain elusive. SGLT2i inhibits proximal tubule (PT) NHE3-mediated sodium reabsorption in normotensive rodents, yet no hypotensive effect is observed under this scenario. This study examined the effect of empagliflozin (EMPA) on renal tubular sodium transport in normotensive and spontaneously hypertensive rats (SHRs). It also tested the hypothesis that EMPA-mediated PT NHE3 inhibition in normotensive rats is associated with upregulation of distal nephron apical sodium transporters. EMPA administration for 14 days reduced BP in 12-wk-old SHRs but not in age-matched Wistar rats. PT NHE3 activity was inhibited by EMPA treatment in both Wistar and SHRs. In Wistar rats, EMPA increased NCC activity, mRNA expression, protein abundance, and phosphorylation levels, but not in SHRs. SHRs showed higher NKCC2 activity and an abundance of cleaved ENaC α and γ subunits compared with Wistar rats, none of which were affected by EMPA. Another set of male Wistar rats was treated with EMPA, the NCC inhibitor hydrochlorothiazide (HCTZ), and EMPA combined with HCTZ or vehicle for 14 days. In these rats, BP reduction was observed only with combined EMPA and HCTZ treatment, not with either drug alone. These findings suggest that NCC upregulation counteracts EMPA-mediated inhibition of PT NHE3 in male normotensive rats, maintaining their baseline BP. Moreover, the reduction of NHE3 activity without further upregulation of major apical sodium transporters beyond the PT may contribute to the BP-lowering effect of SGLT2i in experimental models and patients with hypertension.NEW & NOTEWORTHY This study suggests that reduced NHE3-mediated sodium reabsorption in the renal proximal tubule may account, at least in part, for the BP-lowering effect of SGLT2 inhibitors in the setting of hypertension. It also demonstrates that chronic treatment with SGLT2 inhibitors upregulates NCC activity, phosphorylation, and expression in the distal tubule of normotensive but not hypertensive rats. SGLT2 inhibitor-mediated upregulation of NCC seems crucial to counteract proximal tubule natriuresis in subjects with normal BP.
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Affiliation(s)
- Paulo C Castro
- Laboratório de Genética e Cardiologia Molecular, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, São Paulo, Brazil
| | - Thiago M Santos-Rios
- Laboratório de Genética e Cardiologia Molecular, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, São Paulo, Brazil
| | - Flavia L Martins
- Laboratório de Genética e Cardiologia Molecular, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, São Paulo, Brazil
| | - Renato O Crajoinas
- Laboratório de Genética e Cardiologia Molecular, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, São Paulo, Brazil
| | - Marcos V Caetano
- Laboratório de Genética e Cardiologia Molecular, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, São Paulo, Brazil
| | - Lucília M A Lessa
- Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, Brazil
| | - Weverton M Luchi
- Hospital Universitário Cassiano Antonio Moraes, Universidade Federal do Espírito Santo (HUCAM-UFES), Vitória, Brazil
| | - James A McCormick
- Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon, United States
| | - Adriana C C Girardi
- Laboratório de Genética e Cardiologia Molecular, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, São Paulo, Brazil
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12
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Alsalem A, Alsultan MM, Alqarni F, Almangour A, Alsharekh L, Alenazi S, Alzahrani S, Almanqour RA, Alazmi A, Alzahrani A. Real-world evidence of the effects of sodium-glucose co-transporter 2 inhibitors on the dosing of diuretics in patients with heart failure: a retrospective cohort study. Front Pharmacol 2024; 15:1366439. [PMID: 38628646 PMCID: PMC11018970 DOI: 10.3389/fphar.2024.1366439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 03/07/2024] [Indexed: 04/19/2024] Open
Abstract
Background: Heart failure (HF) was estimated to impact approximately 64 million individuals worldwide in 2017 and is predicted to rise in the coming years. Therefore, the aim of our study was to evaluate the effects of sodium-glucose transport protein 2 (SGLT2) inhibitors on the dosing of diuretics among individuals diagnosed with HF. Methods: A retrospective cohort study was conducted at Security Forces Hospital in Riyadh, Saudi Arabia, between January 2018 and August 2022. The study included adult patients who were diagnosed with heart failure and received dapagliflozin and/or diuretic. A descriptive analysis was conducted to identify significant differences between both groups by using the chi-square test for categorical variables and the Student's t-test for continuous variables. A logistic regression model was also run to identify the odds of each event. Statistical significance was indicated by p values less than .05. Results: Overall reduction in diuretics was reported in 68 patients in the SGLT2 inhibitors plus diuretic therapy group, while in the diuretic therapy group 25 patients reported overall reduction in diuretics (OR = 4.81, 95% [2.74-8.45]). The reduction of the loop dose level was reported by 58 patients in the SGLT2 inhibitors plus diuretic group and by 25 patients in the diuretic group (OR = 3.48, 95% [1.98-6.11]). The discontinuation of thiazide was reported by 16 patients in the SGLT2 inhibitors plus diuretic therapy group, but by only two patients in the diuretic group (OR = 9.04, 95% [2.03-40.19]). After 6 months, ejection fraction was increased by 2.74 in the SGLT2 inhibitors plus diuretic group (p = .0019) and decreased by 2.56 in the diuretic group (p = .0485), both of which were statistically significant. The mean dose changes were decreased by 14.52 in the SGLT2 inhibitors plus diuretic group (p < .0001), which was statistically significant. Conclusion: Treatment with SGLT2 inhibitors plus diuretic significantly reduced the patients' diuretic requirements. Therefore, our finding supports the theoretical concept of minimizing the level of diuretic upon the initiation of SGLT2 inhibitors.
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Affiliation(s)
- Abdulaziz Alsalem
- Department of Pharmacy, Security Forces Hospital, Riyadh, Saudi Arabia
| | - Mohammed M. Alsultan
- Department of Pharmacy Practice, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Faisal Alqarni
- Department of Pharmacy, Security Forces Hospital, Riyadh, Saudi Arabia
| | | | - Lolwa Alsharekh
- Department of Pharmacy, Security Forces Hospital, Riyadh, Saudi Arabia
| | - Saleem Alenazi
- Department of Cardiology, Security Forces Hospital, Riyadh, Saudi Arabia
| | - Saleh Alzahrani
- Department of Pharmacy, Security Forces Hospital, Riyadh, Saudi Arabia
| | | | - Abdullah Alazmi
- College of Medicine Al-Jouf University, Sakaka, Saudi Arabia
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13
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Heerspink HJ, Provenzano M, Vart P, Jongs N, Correa-Rotter R, Rossing P, Mark PB, Pecoits-Filho R, McMurray JJ, Langkilde AM, Wheeler DC, Toto RB, Chertow GM. Dapagliflozin and Blood Pressure in Patients with Chronic Kidney Disease and Albuminuria. Am Heart J 2024; 270:125-135. [PMID: 38367893 DOI: 10.1016/j.ahj.2024.02.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/12/2024] [Accepted: 02/12/2024] [Indexed: 02/19/2024]
Abstract
BACKGROUND AND AIMS Sodium-glucose cotransporter 2 inhibitors decrease blood pressure in patients with type 2 diabetes, but the consistency and magnitude of blood pressure lowering with dapagliflozin in patients with chronic kidney disease (CKD) is unknown. We conducted a prespecified analysis of the DAPA-CKD trial to investigate the effect of dapagliflozin on systolic blood pressure (SBP) in patients with CKD, with and without type 2 diabetes. METHODS A total of 4304 adults with baseline estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g were randomized to either dapagliflozin 10 mg or placebo once daily; median follow-up was 2.4 years. The primary endpoint was a composite of sustained ≥50% eGFR decline, end-stage kidney disease, or death from a kidney or cardiovascular cause. Change in SBP was a prespecified outcome. RESULTS Baseline mean (SD) SBP was 137.1 mmHg (17.4). By Week 2, dapagliflozin compared to placebo reduced SBP by 3.6 mmHg (95% CI 2.8-4.4 mmHg), an effect maintained over the duration of the trial (2.9 mmHg, 2.3-3.6 mmHg). Time-averaged reductions in SBP were 3.2 mmHg (2.5-4.0 mmHg) in patients with diabetes and 2.3 mmHg (1.2-3.4 mmHg) in patients without diabetes. The time-averaged effect of dapagliflozin on diastolic blood pressure (DBP) was 1.0 mmHg (0.6-1.4 mmHg); 0.8 mmHg (0.4-1.3 mmHg) in patients with diabetes and 1.4 mmHg (0.7-2.1 mmHg) in patients without diabetes. Benefits of dapagliflozin on the primary composite and secondary endpoints were evident across the spectrum of baseline SBP and DBP. CONCLUSION In patients with CKD and albuminuria, randomization to dapagliflozin was associated with modest reductions in systolic and diastolic BP.
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Affiliation(s)
- Hiddo Jl Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands; The George Institute for Global Health, Sydney, New South Wales, Australia
| | - Michele Provenzano
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy
| | - Priya Vart
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands; Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Niels Jongs
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Ricardo Correa-Rotter
- The National Medical Science and Nutrition Institute Salvador Zubiran, Mexico City, Mexico
| | - Peter Rossing
- Steno Diabetes Centre Copenhagen, Gentofte, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Patrick B Mark
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK; Renal & Transplant Unit, Queen Elizabeth University Hospital, Glasgow, UK
| | - Roberto Pecoits-Filho
- Arbor Research Collaborative for Health, Ann Arbor, MI; Pontificia Universidade Catolica do Parana, Curitiba, Brazil
| | - John Jv McMurray
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
| | | | - David C Wheeler
- Department of Renal Medicine, University College London, London, UK
| | - Robert B Toto
- Department of Internal Medicine, UT Southwestern Medical Centre, Dallas, TX
| | - Glenn M Chertow
- Department of Medicine, Stanford University School of Medicine, Stanford, CA; Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA; Department of Health Policy, Stanford University School of Medicine, Stanford, CA.
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14
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Palazzuoli A, Ruocco G, Del Buono MG, Pavoncelli S, Delcuratolo E, Abbate A, Lavie CJ. The role and application of current pharmacological management in patients with advanced heart failure. Heart Fail Rev 2024; 29:535-548. [PMID: 38285236 DOI: 10.1007/s10741-024-10383-0] [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] [Accepted: 01/09/2024] [Indexed: 01/30/2024]
Abstract
In the last decades, several classifications and definitions have been proposed for advanced heart failure (ADVHF) patients, including clinical, functional, hemodynamic, imaging, and electrocardiographic features. Despite different inclusion criteria, ADVHF is characterized by some common items, such as drug intolerance, low arterial pressure, multiple organ dysfunction, chronic kidney disease, and diuretic use dependency. Additional features include fatigue, hypotension, hyponatremia, and unintentional weight loss associated with a specific laboratory profile reflecting systemic multiorgan dysfunction. Notably, studies evaluating guideline-directed medical therapy recently endorsed by guidelines in stable HF, including the 4 drug classes all together (i.e., betablocker, mineral corticoid antagonist, renin angiotensin inhibitors/neprilysin inhibitors, and sodium glucose transporter inhibitors), remain scarcely analyzed in ADVHF and New York Heart Association (NYHA) Class IV. Additionally, due to the common conditions associated with advanced stages, the balance between drug tolerance and potential benefits of the contemporary use of all agents is questioned. Therefore, less hard endpoints, such as exercise tolerance, quality of life (QoL) and self-competency, are not clearly demonstrated. Specific analyses evaluating outcome and rehospitalization of each drug provided conflicting results and are often limited to subjects with stable conditions and less advanced NYHA class. Current European Society of Cardiology/American Heart Association (ESC/AHA) Guidelines do not indicate the type of treatment, dosage, and administration modalities, and they do not suggest specific indications for ADVHF patients. Due to these concerns, there is an impelling need to understand what drugs may be used as the first line, what management leads to the better outcome, and what is the best treatment algorithm in this setting. In this paper, we summarize the most common pitfalls and limitations for the use of the traditional agents, and we propose a personalized approach aiming at preserve drug tolerance and maintaining adverse event protection and satisfactory QoL.
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Affiliation(s)
- Alberto Palazzuoli
- Cardiovascular Diseases Unit, Cardiothoracic and Vascular Department, Le Scotte Hospital, University of Siena, Viale Bracci 12, 53100, Siena, Italy.
| | - Gaetano Ruocco
- Cardiology Unit, "Buon Consiglio Hospital" Fatebenefratelli, Naples, Italy
| | - Marco Giuseppe Del Buono
- Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli, Rome, Italy
| | - Simona Pavoncelli
- Cardiovascular Diseases Unit, Cardiothoracic and Vascular Department, Le Scotte Hospital, University of Siena, Viale Bracci 12, 53100, Siena, Italy
| | - Elvira Delcuratolo
- Cardiovascular Diseases Unit, Cardiothoracic and Vascular Department, Le Scotte Hospital, University of Siena, Viale Bracci 12, 53100, Siena, Italy
| | - Antonio Abbate
- Berne Cardiovascular Research Center, Division of Cardiology and Heart and Vascular Center, University of Virginia-School of Medicine, Charlottesville, VA, USA
| | - Carl J Lavie
- John Ochsner Heart and Vascular Institute Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA, USA
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15
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Palmer BF, Clegg DJ. SGLT2 Inhibition and Kidney Potassium Homeostasis. Clin J Am Soc Nephrol 2024; 19:399-405. [PMID: 37639260 PMCID: PMC10937025 DOI: 10.2215/cjn.0000000000000300] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 08/20/2023] [Indexed: 08/29/2023]
Abstract
Pharmacologic inhibition of the sodium-glucose transporter 2 (SGLT2) in the proximal tubule brings about physiologic changes predicted to both increase and decrease kidney K + excretion. Despite these effects, disorders of plasma K + concentration are an uncommon occurrence. If anything, these drugs either cause no effect or a slight reduction in plasma K + concentration in patients with normal kidney function but seem to exert a protective effect against hyperkalemia in the setting of reduced kidney function or when given with drugs that block the renin-angiotensin-aldosterone axis. In this review, we discuss the changes in kidney physiology after the administration of SGLT2 inhibitors predicted to cause both hypokalemia and hyperkalemia. We conclude that these factors offset one another, explaining the uncommon occurrence of dyskalemias with these drugs. Careful human studies focusing on the determinants of kidney K + handling are needed to fully understand how these drugs attenuate the risk of hyperkalemia and yet rarely cause hypokalemia.
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Affiliation(s)
- Biff F. Palmer
- Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
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16
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Palmer BF, Clegg DJ. SGLT2 Inhibition and Tubular Sodium Handling. J Am Soc Nephrol 2024; 35:131-133. [PMID: 38129943 PMCID: PMC10843184 DOI: 10.1681/asn.0000000000000280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023] Open
Affiliation(s)
- Biff F. Palmer
- Internal Medicine, Department of Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Deborah J. Clegg
- Internal Medicine, Vice President for Research, Texas Tech Health Sciences Center, El Paso, Texas
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17
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Rao VS, Ivey-Miranda JB, Cox ZL, Moreno-Villagomez J, Maulion C, Bellumkonda L, Chang J, Field MP, Wiederin DR, Butler J, Collins SP, Turner JM, Wilson FP, Inzucchi SE, Wilcox CS, Ellison DH, Testani JM. Empagliflozin in Heart Failure: Regional Nephron Sodium Handling Effects. J Am Soc Nephrol 2024; 35:189-201. [PMID: 38073038 PMCID: PMC10843196 DOI: 10.1681/asn.0000000000000269] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 10/25/2023] [Indexed: 02/02/2024] Open
Abstract
SIGNIFICANCE STATEMENT The effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on regional tubular sodium handling is poorly understood in humans. In this study, empagliflozin substantially decreased lithium reabsorption in the proximal tubule (PT) (a marker of proximal tubular sodium reabsorption), a magnitude out of proportion to that expected with only inhibition of sodium-glucose cotransporter-2. This finding was not driven by an "osmotic diuretic" effect; however, several parameters changed in a manner consistent with inhibition of the sodium-hydrogen exchanger 3. The large changes in proximal tubular handling were acutely buffered by increased reabsorption in both the loop of Henle and the distal nephron, resulting in the observed modest acute natriuresis with these agents. After 14 days of empagliflozin, natriuresis waned due to increased reabsorption in the PT and/or loop of Henle. These findings confirm in humans that SGLT2i have complex and important effects on renal tubular solute handling. BACKGROUND The effect of SGLT2i on regional tubular sodium handling is poorly understood in humans but may be important for the cardiorenal benefits. METHODS This study used a previously reported randomized, placebo-controlled crossover study of empagliflozin 10 mg daily in patients with diabetes and heart failure. Sodium handling in the PT, loop of Henle (loop), and distal nephron was assessed at baseline and day 14 using fractional excretion of lithium (FELi), capturing PT/loop sodium reabsorption. Assessments were made with and without antagonism of sodium reabsorption through the loop using bumetanide. RESULTS Empagliflozin resulted in a large decrease in sodium reabsorption in the PT (increase in FELi=7.5%±10.6%, P = 0.001), with several observations suggesting inhibition of PT sodium hydrogen exchanger 3. In the absence of renal compensation, this would be expected to result in approximately 40 g of sodium excretion/24 hours with normal kidney function. However, rapid tubular compensation occurred with increased sodium reabsorption both in the loop ( P < 0.001) and distal nephron ( P < 0.001). Inhibition of sodium-glucose cotransporter-2 did not attenuate over 14 days of empagliflozin ( P = 0.14). However, there were significant reductions in FELi ( P = 0.009), fractional excretion of sodium ( P = 0.004), and absolute fractional distal sodium reabsorption ( P = 0.036), indicating that chronic adaptation to SGLT2i results primarily from increased reabsorption in the loop and/or PT. CONCLUSIONS Empagliflozin caused substantial redistribution of intrarenal sodium delivery and reabsorption, providing mechanistic substrate to explain some of the benefits of this class. Importantly, the large increase in sodium exit from the PT was balanced by distal compensation, consistent with SGLT2i excellent safety profile. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER ClinicalTrials.gov ( NCT03027960 ).
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Affiliation(s)
- Veena S. Rao
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Juan B. Ivey-Miranda
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
- Hospital de Cardiologia, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Zachary L. Cox
- Department of Pharmacy Practice, Lipscomb University College of Pharmacy, Nashville, Tennessee
- Department of Pharmacy, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Julieta Moreno-Villagomez
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
- Facultad de Estudios Superiores Iztacala, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
| | - Christopher Maulion
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Lavanya Bellumkonda
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - John Chang
- Section of General Internal Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
- Department of Medicine, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut
| | | | | | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, Texas
| | - Sean P. Collins
- Department of Emergency Medicine, Geriatric Research, Education and Clinical Center (GRECC), Vanderbilt University Medical Center and Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee
| | - Jeffrey M. Turner
- Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - F. Perry Wilson
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
- Clinical and Translational Research Accelerator, Yale University School of Medicine, New Haven, Connecticut
| | - Silvio E. Inzucchi
- Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Christopher S. Wilcox
- Division of Nephrology and Hypertension Center, Georgetown University, Washington, DC
| | - David H. Ellison
- Oregon Clinical and Translational Research Institute, Oregon Health and Science University, Portland, Oregon
| | - Jeffrey M. Testani
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
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18
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Emara AN, Wadie M, Mansour NO, Shams MEE. The clinical outcomes of dapagliflozin in patients with acute heart failure: A randomized controlled trial (DAPA-RESPONSE-AHF). Eur J Pharmacol 2023; 961:176179. [PMID: 37923161 DOI: 10.1016/j.ejphar.2023.176179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 10/31/2023] [Accepted: 11/01/2023] [Indexed: 11/07/2023]
Abstract
AIMS Dapagliflozin may confer additional decongestive and natriuretic benefits to patients with acute heart failure (AHF). Nonetheless, this hypothesis was not clinically examined. This study aimed primarily to investigate the effect of dapagliflozin on symptomatic relief in those patients. METHODS This was a randomized, double-blind study that included 87 patients with AHF presenting with dyspnea. Within 24 h of admission, patients were randomized to receive either dapagliflozin (10 mg/day, N = 45) or placebo (N = 42) for 30 days. The primary outcome was the difference between the two groups in the area under the curve (AUC) of visual analogue scale (VAS) dyspnea score over the first 4 days. Secondary endpoints included urinary sodium (Na) after 2 h of randomization, percent change in NT-proBNP, cumulative urine output (UOP), and differences in mortality and hospital readmission rates. RESULTS The results showed that dapagliflozin significantly reduced the AUC of VAS dyspnea score compared to placebo (3192.2 ± 1631.9 mm × h vs 4713.1 ± 1714.9 mm × h, P < 0.001). The relative change of NT-proBNP compared to its baseline was also larger with dapagliflozin (-34.89% vs -10.085%, P = 0.001). Additionally, higher cumulative UOP was found at day 4 (18600 ml in dapagliflozin vs 13700 in placebo, P = 0.031). Dapagliflozin decreased rehospitalization rates within 30 days after discharge, while it did not affect the spot urinary Na concentration, incidence of worsening of heart failure, or mortality rates. CONCLUSION Dapagliflozin may provide symptomatic relief and improve diuresis in patients with AHF. Further studies are needed to confirm these findings. https://clinicaltrials.gov/study/NCT05406505.
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Affiliation(s)
- Abdelrahman N Emara
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Moheb Wadie
- Cardiology Department, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt.
| | - Noha O Mansour
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Mansoura National University, Egypt.
| | - Mohamed E E Shams
- Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
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19
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Clemmer JS, Yen TE, Obi Y. Modeling the renoprotective mechanisms of SGLT2 inhibition in hypertensive chronic kidney disease. Physiol Rep 2023; 11:e15836. [PMID: 37957121 PMCID: PMC10643202 DOI: 10.14814/phy2.15836] [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: 08/01/2023] [Revised: 09/20/2023] [Accepted: 09/21/2023] [Indexed: 11/15/2023] Open
Abstract
Sodium-glucose cotransporter (SGLT)-2 inhibitors have recently been approved for chronic kidney disease (CKD) based on their ability to lower proteinuria and slow CKD progression independent of diabetes status. In diabetic renal disease, modulation of tubuloglomerular feedback (TGF) leading to lower intraglomerular pressure has been postulated as one of the mechanisms of renal protection with SGLT2 inhibition; however, this mechanism has not been sufficiently explored in non-diabetic CKD. We hypothesized that SGLT2 inhibition exerts renoprotection in CKD through increasing TGF despite normoglycemia. To test this hypothesis, we used an integrative mathematical model of human physiology, HumMod. Stage 3 CKD conditions were simulated by reducing nephron mass which was associated with hypertension, low glomerular filtration rate (GFR) (55 mL/min), hyperfiltration of remnant nephrons, elevated albuminuria (500 mg/day), and minimal levels of urinary glucose (0.02 mmol/L). SGLT2 inhibition was associated with acute reductions in GFR associated with afferent arteriolar vasoconstriction due to TGF. After 12 months, glomerular pressure, nephron damage, and chronic GFR decline were reduced with SGLT2 inhibition with additional SGLT1 inhibitory effects further enhancing these effects. This model supports the use of SGLT2 inhibitors to reduce hyperfiltration in CKD and mitigate renal disease progression, even in the absence of diabetes.
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Affiliation(s)
- John S. Clemmer
- Department of Physiology and BiophysicsUniversity of Mississippi Medical CenterJacksonMississippiUSA
| | - Timothy E. Yen
- Department of Medicine, Division of NephrologyUniversity of Mississippi Medical CenterJacksonMississippiUSA
| | - Yoshitsugu Obi
- Department of Medicine, Division of NephrologyUniversity of Mississippi Medical CenterJacksonMississippiUSA
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20
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Afsar B, Afsar RE. The role of glycosaminoglycans in blood pressure regulation. Microcirculation 2023; 30:e12832. [PMID: 37794746 DOI: 10.1111/micc.12832] [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: 02/01/2023] [Revised: 05/06/2023] [Accepted: 09/23/2023] [Indexed: 10/06/2023]
Abstract
Essential hypertension (HT) is the global health problem and is a major risk factor for the development of cardiovascular and kidney disease. High salt intake has been associated with HT and impaired kidney sodium excretion is considered to be a major mechanism for the development of HT. Although kidney has a very important role in regulation of BP, this traditional view of BP regulation was challenged by recent findings suggesting that nonosmotic tissue sodium deposition is very important for BP regulation. This new paradigm indicates that sodium can be stored and deposited nonosmotically in the interstitium without water retention and without increased BP. One of the major determinants of this deposition is glycosaminoglycans (GAGs). By binding to GAGs found in the endothelial surface layer (ESL) which contains glycocalyx, sodium is osmotically inactivated and not induce concurrent water retention. Thus, GAGs has important function for homeostatic BP and sodium regulation. In the current review, we summarized the role of GAGs in ESL and BP regulation.
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Affiliation(s)
- Baris Afsar
- School of Medicine, Department of Nephrology, Suleyman Demirel University, Isparta, Turkey
| | - Rengin Elsurer Afsar
- School of Medicine, Department of Nephrology, Suleyman Demirel University, Isparta, Turkey
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21
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Al-Tantawy SM, Eraky SM, Eissa LA. Promising renoprotective effect of gold nanoparticles and dapagliflozin in diabetic nephropathy via targeting miR-192 and miR-21. J Biochem Mol Toxicol 2023; 37:e23430. [PMID: 37352119 DOI: 10.1002/jbt.23430] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 03/04/2023] [Accepted: 06/12/2023] [Indexed: 06/25/2023]
Abstract
Diabetic nephropathy (DN) is a worldwide issue that eventually leads to end-stage renal failure, with limited therapeutic options. Prior research has revealed that gold nanoparticles (AuNPs) have a substantial antidiabetic impact. In addition, sodium-glucose cotransporter2 (SGLT2) inhibitors, including dapagliflozin (DAPA), had renoprotective impact on DN. Therefore, this research attempted to determine the potential AuNPs and DAPA impacts in ameliorating experimentally DN induction and the underlying mechanisms focusing on miR-192 and miR-21, correlating them with autophagy, apoptosis, fibrosis, and oxidative stress. Diabetes induction was through a single intraperitoneal streptozotocin (55 mg/kg) injection, and rats with diabetes received AuNPs (2.5 mg/kg/day) as well as DAPA (2 mg/kg/day) for 7 weeks as a treatment. AuNPs and DAPA treatment for 7 weeks substantially alleviated DN. AuNPs and DAPA significantly increased catalase (CAT) activity as well as serum total antioxidant capacity (TAC), along with a substantial decline in malondialdehyde (MDA). AuNPs and DAPA treatment alleviated renal fibrosis as they decreased transforming growth factorß1(TGF-ß1) as well as matrix metalloproteinase-2 (MMP-2) renal expression, decreased apoptosis through alleviating the proapoptotic gene (caspase-3) renal expression and increased the antiapoptotic gene (Bcl-2) renal expression, and increased autophagy as they increased LC-3 as well as Beclin-1 renal expression. Autophagy activation, inhibition of apoptosis, and renal fibrosis could be due to their inhibitory impact on miR-192 and miR-21 renal expression. AuNPs and DAPA have a protective effect on DN in rats by targeting miR-192 and miR-21 and their downstream pathways, including fibrosis, apoptosis, autophagy, and oxidative stress.
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Affiliation(s)
- Samar M Al-Tantawy
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Salma M Eraky
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Laila A Eissa
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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22
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Kazory A. Combination Diuretic Therapy to Counter Renal Sodium Avidity in Acute Heart Failure: Trials and Tribulations. Clin J Am Soc Nephrol 2023; 18:1372-1381. [PMID: 37102974 PMCID: PMC10578637 DOI: 10.2215/cjn.0000000000000188] [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: 02/17/2023] [Accepted: 04/20/2023] [Indexed: 04/28/2023]
Abstract
In contrast to significant advances in the management of patients with chronic heart failure over the past few years, there has been little change in how patients with acute heart failure are treated. Symptoms and signs of fluid overload are the primary reason for hospitalization of patients who experience acute decompensation of heart failure. Intravenous loop diuretics remain the mainstay of therapy in this patient population, with a significant subset of them showing suboptimal response to these agents leading to incomplete decongestion at the time of discharge. Combination diuretic therapy, that is, using loop diuretics along with an add-on agent, is a widely applied strategy to counter renal sodium avidity through sequential blockade of sodium absorption within renal tubules. The choice of the second diuretic is affected by several factors, including the site of action, the anticipated secondary effects, and the available evidence on their efficacy and safety. While the current guidelines recommend combination diuretic therapy as a viable option to overcome suboptimal response to loop diuretics, it is also acknowledged that this strategy is not supported by strong evidence and remains an area of uncertainty. The recent publication of landmark studies has regenerated the interest in sequential nephron blockade. In this article, we provide an overview of the results of the key studies on combination diuretic therapy in the setting of acute heart failure and discuss their findings primarily with regard to the effect on renal sodium avidity and cardiorenal outcomes.
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Affiliation(s)
- Amir Kazory
- Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, Gainesville, Florida
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23
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Asrial AA, Reviono R, Soetrisno S, Setianto BY, Widyaningsih V, Nurwati I, Wasita B, Pudjiastuti A. Effect of Dapagliflozin on Patients with Rheumatic Heart Disease Mitral Stenosis. J Clin Med 2023; 12:5898. [PMID: 37762839 PMCID: PMC10532082 DOI: 10.3390/jcm12185898] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 08/31/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
(1) Background: Mitral stenosis is the most common rheumatic heart disease (RHD). Inflammation and fibrosis are the primary pathophysiology, resulting in left atrial stress and dysfunction. Dapagliflozin is a new heart failure treatment with anti-inflammation and anti-fibrosis effects from previous studies. However, the specific role of dapagliflozin in RHD mitral stenosis is unknown. This study aims to investigate (i) the effect of dapagliflozin on biomarkers of fibrosis, NT-pro BNP levels and left atrial function; (ii) the relationship between the changes in fibrosis biomarkers with left atrial function and NT-pro BNP levels. (2) Methods: An open-label randomized study was conducted on 33 RHD mitral stenosis patients divided into a dapagliflozin group which received 10 mg dapagliflozin and standard therapy, and a control group which only received standard therapy. All patients were examined for levels of PICP, MMP-1/TIMP-1 ratio, TGF-β1, NT-proBNP, mitral valve mean pressure gradient (MPG), and net atrioventricular compliance (Cn) pre- and post-intervention. (3) Results: This study found a significant increase in PICP and TGF-β1 and a reduction in the MMP-1/TIMP-1 ratio in the dapagliflozin group and the control group (p < 0.05). In the dapagliflozin group, the levels of NT-pro BNP decreased significantly (p = 0.000), with a delta of decreased NT-pro BNP levels also significantly greater in the dapagliflozin group compared to the control (p = 0.034). There was a significant increase in Cn values in the dapagliflozin group (p = 0.017), whereas there was a decrease in the control group (p = 0.379). Delta of changes in Cn values between the dapagliflozin and control groups also showed a significant value (p = 0.049). The decreased MPG values of the mitral valve were found in both the dapagliflozin and control groups, with the decrease in MPG significantly greater in the dapagliflozin group (p = 0.031). There was no significant correlation between changes in the value of fibrosis biomarkers with Cn and NT-pro BNP (p > 0.05). (4) Conclusions: This study implies that the addition of dapagliflozin to standard therapy for RHD mitral stenosis patients provides benefits, as evidenced by an increase in net atrioventricular compliance and decreases in the MPG value of the mitral valve and NT-pro BNP levels (p < 0.05). This improvement was not directly related to changes in fibrosis biomarkers, as these biomarkers showed ongoing fibrosis even with dapagliflozin administration.
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Affiliation(s)
- An Aldia Asrial
- Doctoral Program of Medical Sciences Department, Faculty of Medicine, Universitas Sebelas Maret, Surakarta 57126, Indonesia
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Sebelas Maret—Universitas Sebelas Maret Hospital, Surakarta 57126, Indonesia
| | - Reviono Reviono
- Doctoral Program of Medical Sciences Department, Faculty of Medicine, Universitas Sebelas Maret, Surakarta 57126, Indonesia
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Sebelas Maret—Universitas Sebelas Maret Hospital, Surakarta 57126, Indonesia
| | - Soetrisno Soetrisno
- Doctoral Program of Medical Sciences Department, Faculty of Medicine, Universitas Sebelas Maret, Surakarta 57126, Indonesia
- Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Sebelas Maret—Universitas Sebelas Maret Hospital, Surakarta 57126, Indonesia
| | - Budi Yuli Setianto
- Doctoral Program of Medical Sciences Department, Faculty of Medicine, Universitas Sebelas Maret, Surakarta 57126, Indonesia
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Gadjah Mada—Dr. Sardjito General Hospital, Yogyakarta 55281, Indonesia
| | - Vitri Widyaningsih
- Doctoral Program of Medical Sciences Department, Faculty of Medicine, Universitas Sebelas Maret, Surakarta 57126, Indonesia
- Department of Public Health, Faculty of Medicine, Universitas Sebelas Maret, Surakarta 57126, Indonesia
| | - Ida Nurwati
- Doctoral Program of Medical Sciences Department, Faculty of Medicine, Universitas Sebelas Maret, Surakarta 57126, Indonesia
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Sebelas Maret, Surakarta 57126, Indonesia
| | - Brian Wasita
- Doctoral Program of Medical Sciences Department, Faculty of Medicine, Universitas Sebelas Maret, Surakarta 57126, Indonesia
- Department of Pathology, Faculty of Medicine, Universitas Sebelas Maret, Surakarta 57126, Indonesia
| | - Anggit Pudjiastuti
- Department of Cardiology and Vascular Medicine, Permata Bunda Hospital, Purwodadi 58114, Indonesia
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Biegus J, Fudim M, Salah HM, Heerspink HJL, Voors AA, Ponikowski P. Sodium-glucose cotransporter-2 inhibitors in heart failure: Potential decongestive mechanisms and current clinical studies. Eur J Heart Fail 2023; 25:1526-1536. [PMID: 37477086 DOI: 10.1002/ejhf.2967] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/19/2023] [Accepted: 07/01/2023] [Indexed: 07/22/2023] Open
Abstract
Congestion is a key pathophysiological feature of heart failure (HF) syndrome that drives most of the clinical manifestations of acute HF and is related with poor quality of life and outcomes. Therefore, safe and effective decongestion is an important therapeutic target in the management of acute HF and despite the use of guideline-recommended loop diuretics, adequate decongestion is not always achieved in patients with acute HF. Recently, sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been shown to provide clinical benefits across a broad spectrum of patients with HF, including consistent reduction in the risk of acute HF episodes. While the exact mechanisms underlying these benefits remain a matter of debate, a growing body of evidence suggests that effective decongestion may be partly responsible, especially in the setting of acute HF. In this review, we discuss the potential decongestive mechanisms of SGLT-2 inhibitors, such as osmotic diuresis, natriuresis, preservation of glomerular filtration and facilitation of interstitial drainage, which can collectively translate into effective and safe decongestion. Furthermore, we provide a comprehensive review of up-to-date clinical data of SGLT-2 inhibitor use in the acute HF population.
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Affiliation(s)
- Jan Biegus
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
| | - Marat Fudim
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
- Department of Medicine, Duke University, Durham, NC, USA
- Duke Clinical Research Institute, Durham, NC, USA
| | - Husam M Salah
- Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Adriaan A Voors
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Piotr Ponikowski
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
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25
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Packer M, Butler J. Similarities and distinctions between acetazolamide and sodium-glucose cotransporter 2 inhibitors in patients with acute heart failure: Key insights into ADVOR and EMPULSE. Eur J Heart Fail 2023; 25:1537-1543. [PMID: 37403655 DOI: 10.1002/ejhf.2968] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 06/26/2023] [Accepted: 07/02/2023] [Indexed: 07/06/2023] Open
Abstract
Both acetazolamide and sodium-glucose cotransporter 2 (SGLT2) inhibitors block sodium reabsorption in the proximal renal tubule primarily through inhibition of sodium-hydrogen exchanger isoform 3 (NHE3), but neither SGLT2 inhibitors nor acetazolamide produce a sustained natriuresis due to compensatory upregulation of sodium reabsorption at distal nephron sites. Nevertheless, acetazolamide and SGLT2 inhibitors have been used as adjunctive therapy to loop diuretics in states where NHE3 is upregulated, e.g. acute heart failure. Two randomized controlled trials have been carried out with acetazolamide in acute heart failure (DIURESIS-CHF and ADVOR). In ADVOR, acetazolamide improved physical signs of fluid retention, but this finding could not be explained by the modest observed diuretic effect. Acetazolamide did not produce a natriuresis in the DIURESIS-CHF trial, and in ADVOR, immediate effects on symptoms and body weight were not reported, and the drug had no effect on morbidity or mortality after 90 days. Three randomized controlled trials have been carried out with empagliflozin (EMPAG-HF, EMPA-RESPONSE-AHF and EMPULSE) in acute heart failure. The EMPULSE trial did not report effects on diuresis or in changes in physical signs of congestion during the first week of treatment, but in EMPAG-HF and EMPA-RESPONSE-AHF, empagliflozin had no effect of dyspnoea, urinary sodium excretion or body weight during the first 4 days. In the EMPULSE trial, empagliflozin improved health status at 15 days and reduced the risk of worsening heart failure events at 90 days, but these effects are similar in magnitude and time course to the early statistical significance on the risk of heart failure hospitalizations achieved within 14-30 days in the major trials of SGLT2 inhibitors in patients with chronic heart failure. Neurohormonal inhibitors produce this early effect in the absence of a diuresis. Additionally, in numerous randomized controlled trials, in-hospital diuretic intensification has not reduced the risk of major heart failure events, even when treatment is sustained. These findings, taken collectively, suggest that any immediate diuretic effects of acetazolamide and SGLT2 inhibitors in acute heart failure are not likely to influence the short- or long-term clinical course of patients.
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Affiliation(s)
- Milton Packer
- Baylor University Medical Center, Dallas, TX, USA
- Imperial College, London, UK
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, TX, USA
- Department of Medicine, University of Mississippi School of Medicine, Jackson, MS, USA
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26
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Packer M. Lack of durable natriuresis and objective decongestion following SGLT2 inhibition in randomized controlled trials of patients with heart failure. Cardiovasc Diabetol 2023; 22:197. [PMID: 37533009 PMCID: PMC10399057 DOI: 10.1186/s12933-023-01946-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 07/28/2023] [Indexed: 08/04/2023] Open
Abstract
Patients with heart failure have increased cardiac filling pressures, circulating natriuretic peptides, and physical signs of fluid retention, which are related to sodium retention by the kidneys and are alleviated by conventional diuretics. Sodium-glucose cotransporter 2 (SGLT2) inhibitors interfere with sodium and glucose reabsorption in the proximal renal tubule, but they evoke a marked counterregulatory activation of sodium and water reabsorption in distal nephron segments, which opposes and negates any diuretic effect. Nevertheless, it has been postulated that SGLT2 inhibitors modulate the volume set point, leading selectively to decongestion in patients with fluid overload. This hypothesis was tested in a review of 15 randomized controlled trials of SGLT2 inhibitors in patients with heart failure, with 7 trials focusing on urinary volume within the first week, and 8 trials focusing on objective decongestion at 12 weeks. In trials < 1 week, SGLT2 inhibition increased urine volume in the first 24 h, but typically without a change in urinary sodium excretion, and this diuresis was not sustained. In 8 trials of 12 weeks' duration, none reported alleviation of edema, ascites or pulmonary rales. The 2 trials that evaluated changes in left ventricular filling pressure noted no or small changes (1-2 mm Hg); the two trials that measured interstitial lung water or total blood volume found no effect; and 6 of the 7 trials found no decrease in circulating natriuretic peptides. Therefore, randomized controlled trials do not indicate that SGLT2 inhibitors produce a durable natriuresis or objective decongestion in patients with heart failure.
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Affiliation(s)
- Milton Packer
- Heart and Vascular Institute, Baylor University Medical Center, 621 North Hall Street, Dallas, TX, 75226, USA.
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27
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Packer M, Wilcox CS, Testani JM. Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes. Circulation 2023; 148:354-372. [PMID: 37486998 PMCID: PMC10358443 DOI: 10.1161/circulationaha.123.064346] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 05/25/2023] [Indexed: 07/26/2023]
Abstract
SGLT2 (sodium-glucose cotransporter 2) inhibitors interfere with the reabsorption of glucose and sodium in the early proximal renal tubule, but the magnitude and duration of any ensuing natriuretic or diuretic effect are the result of an interplay between the degree of upregulation of SGLT2 and sodium-hydrogen exchanger 3, the extent to which downstream compensatory tubular mechanisms are activated, and (potentially) the volume set point in individual patients. A comprehensive review and synthesis of available studies reveals several renal response patterns with substantial variation across studies and clinical settings. However, the common observation is an absence of a large acute or chronic diuresis or natriuresis with these agents, either when given alone or combined with other diuretics. This limited response results from the fact that renal compensation to these drugs is rapid and nearly complete within a few days or weeks, preventing progressive volume losses. Nevertheless, the finding that fractional excretion of glucose and lithium (the latter being a marker of proximal sodium reabsorption) persists during long-term treatment with SGLT2 inhibitors indicates that pharmacological tolerance to the effects of these drugs at the level of the proximal tubule does not meaningfully occur. This persistent proximal tubular effect of SGLT2 inhibitors can be hypothesized to produce a durable improvement in the internal set point for volume homeostasis, which may become clinically important during times of fluid expansion. However, it is difficult to know whether a treatment-related change in the volume set point actually occurs or contributes to the effect of these drugs to reduce the risk of major heart failure events. SGLT2 inhibitors exert cardioprotective effects by a direct effect on cardiomyocytes that is independent of the presence of or binding to SGLT2 or the actions of these drugs on the proximal renal tubule. Nevertheless, changes in the volume set point mediated by SGLT2 inhibitors might potentially act cooperatively with the direct favorable molecular and cellular effects of these drugs on cardiomyocytes to mediate their benefits on the development and clinical course of heart failure.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Dallas, TX (M.P.)
- Imperial College London, United Kingdom (M.P.)
| | - Christopher S. Wilcox
- Division of Nephrology and Hypertension, Kidney, and Vascular Research Center, Georgetown University, Washington, DC (C.S.W.)
| | - Jeffrey M. Testani
- Section of Cardiovascular Medicine, Yale University, New Haven, CT (J.M.T.)
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28
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Gronda E, Palazzuoli A, Iacoviello M, Benevenuto M, Gabrielli D, Arduini A. Renal Oxygen Demand and Nephron Function: Is Glucose a Friend or Foe? Int J Mol Sci 2023; 24:9957. [PMID: 37373108 PMCID: PMC10298324 DOI: 10.3390/ijms24129957] [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: 04/26/2023] [Revised: 06/02/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
The kidneys and heart work together to balance the body's circulation, and although their physiology is based on strict inter dependence, their performance fulfills different aims. While the heart can rapidly increase its own oxygen consumption to comply with the wide changes in metabolic demand linked to body function, the kidneys physiology are primarily designed to maintain a stable metabolic rate and have a limited capacity to cope with any steep increase in renal metabolism. In the kidneys, glomerular population filters a large amount of blood and the tubular system has been programmed to reabsorb 99% of filtrate by reabsorbing sodium together with other filtered substances, including all glucose molecules. Glucose reabsorption involves the sodium-glucose cotransporters SGLT2 and SGLT1 on the apical membrane in the proximal tubular section; it also enhances bicarbonate formation so as to preserve the acid-base balance. The complex work of reabsorption in the kidney is the main factor in renal oxygen consumption; analysis of the renal glucose transport in disease states provides a better understanding of the renal physiology changes that occur when clinical conditions alter the neurohormonal response leading to an increase in glomerular filtration pressure. In this circumstance, glomerular hyperfiltration occurs, imposing a higher metabolic demand on kidney physiology and causing progressive renal impairment. Albumin urination is the warning signal of renal engagement over exertion and most frequently heralds heart failure development, regardless of disease etiology. The review analyzes the mechanisms linked to renal oxygen consumption, focusing on sodium-glucose management.
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Affiliation(s)
- Edoardo Gronda
- Medicine and Medicine Sub-Specialties Department, Cardio Renal Program, U.O.C. Nephrology, Dialysis and Adult Renal Transplant Program, IRCCS Ca’ Granda Foundation, Ospedale Maggiore Policlinico, 20122 Milano, Italy
| | - Alberto Palazzuoli
- Cardiovascular Diseases Unit, Cardio Thoracic and Vascular Department, S. Maria alle Scotte Hospital University of Siena, 53100 Siena, Italy;
| | - Massimo Iacoviello
- Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy
| | - Manuela Benevenuto
- Unità Operativa Complessa Cardiologia-UTIC-Emodinamica, PO Giuseppe Mazzini, 64100 Teramo, Italy;
| | - Domenico Gabrielli
- Unità Operativa Complessa Cardiologia-UTIC, Azienda Ospedaliera San Camillo Forlanini, 00152 Rome, Italy;
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29
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Tang H, Xu C, Zhang P, Luo T, Huang Y, Yang X. A profile of SGLT-2 inhibitors in hyponatremia: The evidence to date. Eur J Pharm Sci 2023; 184:106415. [PMID: 36870579 DOI: 10.1016/j.ejps.2023.106415] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 02/14/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023]
Abstract
Hyponatremia is the most common electrolyte disorder in clinical practice, which may lead to life-threatening complications. Several lines of evidence suggest that hyponatremia is associated not only with significant increases in length of stay, cost, and financial burden, but also with increased morbidity and mortality. Hyponatremia is also considered to be a negative prognostic factor in patients with heart failure and cancer. Although multiple therapeutic methods are available for treating hyponatremia, most have some limitations, such as poor compliance, rapid correction of serum Na+, other negative side effects and high cost. Given these limitations, identifying novel therapies for hyponatremia is essential. Recent clinical studies have shown that SGLT-2 inhibitors (SGLT 2i) significantly increased serum Na+ levels and were well tolerated by patients who underwent this treatment. Therefore, oral administration of SGLT 2i appears to be an effective treatment for hyponatremia. This article will briefly review the etiology of hyponatremia and integrated control of sodium within the kidney, current therapies for hyponatremia, potential mechanisms and efficacy of SGLT 2i for hyponatremia, and the benefits in cardiovascular, cancer, and kidney disease by regulating sodium and water balance.
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Affiliation(s)
- Hui Tang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; School of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Changjing Xu
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Piao Zhang
- Department of Pharmacy, Ya 'an People's Hospital, Ya 'an, Sichuan 646000, China
| | - Taimin Luo
- Department of pharmacy, Chengdu Seventh People's Hospital, Chengdu, Sichuan 610000, China
| | - Yilan Huang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
| | - Xuping Yang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
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Yu W, Xie D, Yamamoto T, Koyama H, Cheng J. Mechanistic insights of soluble uric acid-induced insulin resistance: Insulin signaling and beyond. Rev Endocr Metab Disord 2023; 24:327-343. [PMID: 36715824 DOI: 10.1007/s11154-023-09787-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/10/2023] [Indexed: 01/31/2023]
Abstract
Hyperuricemia is a metabolic disease caused by purine nucleotide metabolism disorder. The prevalence of hyperuricemia is increasing worldwide, with a growing trend in the younger populations. Although numerous studies have indicated that hyperuricemia may be an independent risk factor for insulin resistance, the causal relationship between the two is controversial. There are few reviews, however, focusing on the relationship between uric acid (UA) and insulin resistance from experimental studies. In this review, we summarized the experimental models related to soluble UA-induced insulin resistance in pancreas and peripheral tissues, including skeletal muscles, adipose tissue, liver, heart/cardiomyocytes, vascular endothelial cells and macrophages. In addition, we summarized the research advances about the key mechanism of UA-induced insulin resistance. Moreover, we attempt to identify novel targets for the treatment of hyperuricemia-related insulin resistance. Lastly, we hope that the present review will encourage further researches to solve the chicken-and-egg dilemma between UA and insulin resistance, and provide strategies for the pathogenesis and treatment of hyperuricemia related metabolic diseases.
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Affiliation(s)
- Wei Yu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - De Xie
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Tetsuya Yamamoto
- Health Evaluation Center, Osaka Gyoumeikan Hospital, Osaka, Japan
| | - Hidenori Koyama
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Jidong Cheng
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo Medical University, Nishinomiya, Hyogo, Japan.
- Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, Fujian, China.
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, Fujian, People's Republic of China.
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Van Beusecum JP, Rianto F, Teakell J, Kon V, Sparks MA, Hoorn EJ, Kirabo A, Ramkumar N. Novel Concepts in Nephron Sodium Transport: A Physiological and Clinical Perspective. ADVANCES IN KIDNEY DISEASE AND HEALTH 2023; 30:124-136. [PMID: 36868728 DOI: 10.1053/j.akdh.2022.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/15/2022] [Accepted: 12/15/2022] [Indexed: 04/13/2023]
Abstract
The kidneys play a critical role in maintaining total body sodium (Na+) balance across a wide range of dietary intake, accomplished by a concerted effort involving multiple Na+ transporters along the nephron. Furthermore, nephron Na+ reabsorption and urinary Na+ excretion are closely linked to renal blood flow and glomerular filtration such that perturbations in either of them can modify Na+ transport along the nephron, ultimately resulting in hypertension and other Na+-retentive states. In this article, we provide a brief physiological overview of nephron Na+ transport and illustrate clinical syndromes and therapeutic agents that affect Na+ transporter function. We highlight recent advances in kidney Na+ transport, particularly the role of immune cells, lymphatics, and interstitial Na+ in regulating Na+ reabsorption, the emergence of potassium (K+) as a regulator of Na+ transport, and the evolution of the nephron to modulate Na+ transport.
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Affiliation(s)
- Justin P Van Beusecum
- Ralph H. Johnson VA Medical Center, Charleston, SC; Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, SC
| | - Fitra Rianto
- Division of Nephrology, Department of Medicine, Duke University School of Medicine and Renal Section, Durham VA Health Care System Durham, Durham, NC
| | - Jade Teakell
- Division of Renal Diseases and Hypertension, Department of Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX
| | - Valentina Kon
- Division of Nephrology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN
| | - Matthew A Sparks
- Division of Nephrology, Department of Medicine, Duke University School of Medicine and Renal Section, Durham VA Health Care System Durham, Durham, NC
| | - Ewout J Hoorn
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Annet Kirabo
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
| | - Nirupama Ramkumar
- Division of Nephrology and Hypertension, Department of Medicine, University of Utah Health, Salt Lake City, UT.
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Guo L, Fu B, Liu Y, Hao N, Ji Y, Yang H. Diuretic resistance in patients with kidney disease: Challenges and opportunities. Biomed Pharmacother 2023; 157:114058. [PMID: 36473405 DOI: 10.1016/j.biopha.2022.114058] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 11/15/2022] [Accepted: 11/27/2022] [Indexed: 12/10/2022] Open
Abstract
Edema caused by kidney disease is called renal edema. Edema is a common symptom of many human kidney diseases. Patients with renal edema often need to take diuretics.However, After taking diuretics, patients with kidney diseases are prone to kidney congestion, decreased renal perfusion, decreased diuretics secreted by renal tubules, neuroendocrine system abnormalities, abnormal ion transporter transport, drug interaction, electrolyte disorder, and hypoproteinemia, which lead to ineffective or weakened diuretic use and increase readmission rate and mortality. The main causes and coping strategies of diuretic resistance in patients with kidney diseases were described in detail in this report. The common causes of DR included poor diet (electrolyte disturbance and hypoproteinemia due to patients' failure to limit diet according to correct sodium, chlorine, potassium, and protein level) and poor drug compliance (the patient did not take adequate doses of diuretics. true resistance occurs only if the patient takes adequate doses of diuretics, but they are not effective), changes in pharmacokinetics and pharmacodynamics, electrolyte disorders, changes in renal adaptation, functional nephron reduction, and decreased renal blood flow. Common treatment measures include increasing in the diuretic dose and/or frequency, sequential nephron blockade,using new diuretics, ultrafiltration treatment, etc. In clinical work, measures should be taken to prevent or delay the occurrence and development of DR in patients with kidney diseases according to the actual situation of patients and the mechanism of various causes. Currently, there are many studies on DR in patients with heart diseases. Although the phenomenon of DR in patients with kidney diseases is common, there is a relatively little overview of the mechanism and treatment strategy of DR in patients with kidney diseases. Therefore, this paper hopes to show the information on DR in patients with kidney diseases to clinicians and researchers and broaden the research direction and ideas to a certain extent.
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Affiliation(s)
- Luxuan Guo
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300193, China; Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Baohui Fu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300193, China; Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yang Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300193, China; Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Na Hao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300193, China; Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yue Ji
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300193, China; Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Hongtao Yang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300193, China; Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
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Elrakaybi A, Laubner K, Zhou Q, Hug MJ, Seufert J. Cardiovascular protection by SGLT2 inhibitors - Do anti-inflammatory mechanisms play a role? Mol Metab 2022; 64:101549. [PMID: 35863639 PMCID: PMC9352970 DOI: 10.1016/j.molmet.2022.101549] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 07/04/2022] [Accepted: 07/12/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Metabolic syndrome and related metabolic disturbances represent a state of low-grade inflammation, which accelerates insulin resistance, type 2 diabetes (T2D) and cardiovascular disease (CVD) progression. Among antidiabetic medications, sodium glucose co-transporter (SGLT) 2 inhibitors are the only agents which showed remarkable reductions in heart failure (HF) hospitalizations and major cardiovascular endpoints (MACE) as well as renal endpoints regardless of diabetes status in large randomized clinical outcome trials (RCTs). Although the exact mechanisms underlying these benefits are yet to be established, growing evidence suggests that modulating inflammation by SGLT2 inhibitors may play a key role. SCOPE OF REVIEW In this manuscript, we summarize the current knowledge on anti-inflammatory effects of SGLT2 inhibitors as one of the mechanisms potentially mediating their cardiovascular (CV) benefits. We introduce the different metabolic and systemic actions mediated by these agents which could mitigate inflammation, and further present the signalling pathways potentially responsible for their proposed direct anti-inflammatory effects. We also discuss controversies surrounding some of these mechanisms. MAJOR CONCLUSIONS SGLT2 inhibitors are promising anti-inflammatory agents by acting either indirectly via improving metabolism and reducing stress conditions or via direct modulation of inflammatory signalling pathways. These effects were achieved, to a great extent, in a glucose-independent manner which established their clinical use in HF patients with and without diabetes.
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Affiliation(s)
- Asmaa Elrakaybi
- Division of Endocrinology and Diabetology, Department of Medicine II, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; Department of Clinical Pharmacy, Ain Shams University, 11566 Cairo, Egypt
| | - Katharina Laubner
- Division of Endocrinology and Diabetology, Department of Medicine II, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Qian Zhou
- Department of Cardiology and Angiology I, Heart Centre, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; Department of Cardiology, University Hospital Basel, 4031 Basel, Switzerland
| | - Martin J Hug
- Pharmacy, Medical Centre - University of Freiburg, 79106 Freiburg, Germany
| | - Jochen Seufert
- Division of Endocrinology and Diabetology, Department of Medicine II, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
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Gliozzi M, Macrì R, Coppoletta AR, Musolino V, Carresi C, Scicchitano M, Bosco F, Guarnieri L, Cardamone A, Ruga S, Scarano F, Nucera S, Mollace R, Bava I, Caminiti R, Serra M, Maiuolo J, Palma E, Mollace V. From Diabetes Care to Heart Failure Management: A Potential Therapeutic Approach Combining SGLT2 Inhibitors and Plant Extracts. Nutrients 2022; 14:nu14183737. [PMID: 36145112 PMCID: PMC9504067 DOI: 10.3390/nu14183737] [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: 05/09/2022] [Revised: 09/06/2022] [Accepted: 09/07/2022] [Indexed: 11/30/2022] Open
Abstract
Diabetes is a complex chronic disease, and among the affected patients, cardiovascular disease (CVD)is the most common cause of death. Consequently, the evidence for the cardiovascular benefit of glycaemic control may reduce long-term CVD rates. Over the years, multiple pharmacological approaches aimed at controlling blood glucose levels were unable to significantly reduce diabetes-related cardiovascular events. In this view, a therapeutic strategy combining SGLT2 inhibitors and plant extracts might represent a promising solution. Indeed, countering the main cardiometabolic risk factor using plant extracts could potentiate the cardioprotective action of SGLT2 inhibitors. This review highlights the main molecular mechanisms underlying these beneficial effects that could contribute to the better management of diabetic patients.
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Affiliation(s)
- Micaela Gliozzi
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Roberta Macrì
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Anna Rita Coppoletta
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Vincenzo Musolino
- Pharmaceutical Biology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
- Correspondence: (V.M.); (C.C.); Tel./Fax: +39-0961-3694301 (V.M. & C.C.)
| | - Cristina Carresi
- Veterinary Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
- Correspondence: (V.M.); (C.C.); Tel./Fax: +39-0961-3694301 (V.M. & C.C.)
| | - Miriam Scicchitano
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Francesca Bosco
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Lorenza Guarnieri
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Antonio Cardamone
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Stefano Ruga
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Federica Scarano
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Saverio Nucera
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Rocco Mollace
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Irene Bava
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Rosamaria Caminiti
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Maria Serra
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Jessica Maiuolo
- Pharmaceutical Biology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Ernesto Palma
- Veterinary Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
| | - Vincenzo Mollace
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
- Renato Dulbecco Institute, Lamezia Terme, 88046 Catanzaro, Italy
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Zhang Y, Han Q. A review of cardiovascular benefits of SGLT2 inhibitors. Medicine (Baltimore) 2022; 101:e30310. [PMID: 36086785 PMCID: PMC10980435 DOI: 10.1097/md.0000000000030310] [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: 06/08/2022] [Accepted: 06/17/2022] [Indexed: 11/26/2022] Open
Abstract
Sodium-glucose cotransporter 2 inhibitor (SGLT2I) is a new type of hypoglycemic drug that targets the kidney. As research continues to advance on this topic, it has been found that SGLT2I has multiple protective effects, such as hypoglycemic, cardio-renal protective, antihypertensive, and lipid-lowering effects. This review discusses the current concepts and possible mechanisms of SGLT2I in the treatment of heart failure, myocardial infarction, hypertension, cardiomyopathy and arrhythmia to provide a reference for clinicians to use drugs more reasonably and scientifically.
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Affiliation(s)
- Yingxia Zhang
- First Department of Clinical Medicine, Shanxi Medical University, Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Province, China
| | - Qinghua Han
- Department of Cardiology, The 1st Hospital of Shanxi Medical University, Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Province, China
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He X, Gao X, Xie P, Liu Y, Bai W, Liu Y, Shi A. Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Sotagliflozin After Multiple Ascending Doses in Chinese Healthy Subjects. Drug Des Devel Ther 2022; 16:2967-2980. [PMID: 36097559 PMCID: PMC9464004 DOI: 10.2147/dddt.s372575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 08/13/2022] [Indexed: 11/23/2022] Open
Abstract
Background Sotagliflozin (LX4211) is a dual inhibitor of sodium-glucose cotransporter (SGLT)1 and SGLT2 being investigated to improve glycemic control in adults with diabetes. This study was firstly conducted to assess the pharmacokinetic (PK), pharmacodynamic (PD) profiles, safety and tolerability in Chinese healthy subjects after administration of sotagliflozin. Methods This was a Phase I, randomized, double-blind, placebo-controlled, ascending multiple-dose study. Healthy subjects received 200mg or 400mg of sotagliflozin or placebo once daily for 8 days, respectively. PK parameters of sotagliflozin and LX4211-GLU (main metabolite), as measured by blood samples collected pre/postdose on Day 1/predose on Day 2-Day 8/postdose on Day 8, and PD parameters of absolute urinary glucose excretion (UGE) were determined. Treatment-emergent adverse events (TEAEs) were evaluated. Results Overall, 24 subjects were enrolled and randomized to sotagliflozin 200 mg (N = 9), sotagliflozin 400 mg (N = 9), or placebo (N = 6) group, and all subjects completed the study. Sotagliflozin was rapidly absorbed with dose-proportional systemic exposure and a moderate degree (less than 2-fold) of accumulation. Sotagliflozin plasma concentrations peaked at 1.0 h post dose. On Day 8, the estimated increases for Cmax and AUCtau were 1.89-fold and 1.70-fold. The pooled accumulation ratio of sotagliflozin was 1.57 for Cmax and 1.84 for AUCtau. LX4211-GLU had similar PK features. UGE was significantly elevated in both sotagliflozin groups relative to the placebo group. All TEAEs were mild and resolved without sequelae. There were no serious AEs or other significant TEAEs. Conclusion Sotagliflozin was rapidly absorbed with dose-proportional systemic exposure and a moderate degree of accumulation. Both 200 mg and 400 mg sotagliflozin per day were well tolerated in Chinese healthy subjects.
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Affiliation(s)
- Xuemei He
- Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
| | - Xin Gao
- Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
| | - Panpan Xie
- Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
| | - Yuan Liu
- Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
| | - Wenjing Bai
- Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
| | - Yue Liu
- Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
| | - Aixin Shi
- Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China
- Correspondence: Aixin Shi, Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 Dahua Road, Dongcheng District, Beijing, 100730, People’s Republic of China, Tel +86 10 85133632, Email
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Sen T, Scholtes R, Greasley PJ, Cherney DZI, Dekkers CCJ, Vervloet M, Danser AHJ, Barbour SJ, Karlsson C, Hammarstedt A, Li Q, Laverman GD, Bjornstad P, van Raalte DH, Heerspink HJL. Effects of dapagliflozin on volume status and systemic haemodynamics in patients with chronic kidney disease without diabetes: Results from DAPASALT and DIAMOND. Diabetes Obes Metab 2022; 24:1578-1587. [PMID: 35478433 PMCID: PMC9262818 DOI: 10.1111/dom.14729] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/15/2022] [Accepted: 04/26/2022] [Indexed: 12/30/2022]
Abstract
AIMS To assess the effect of sodium-glucose cotransporter-2 inhibitor dapagliflozin on natriuresis, blood pressure (BP) and volume status in patients with chronic kidney disease (CKD) without diabetes. MATERIALS AND METHODS We performed a mechanistic open-label study (DAPASALT) to evaluate the effects of dapagliflozin on 24-hour sodium excretion, 24-hour BP, extracellular volume, and markers of volume status during a standardized sodium diet (150 mmol/d) in six patients with CKD. In parallel, in a placebo-controlled double-blind crossover trial (DIAMOND), we determined the effects of 6 weeks of dapagliflozin on markers of volume status in 53 patients with CKD. RESULTS In DAPASALT (mean age 65 years, mean estimated glomerular filtration rate [eGFR] 39.4 mL/min/1.73 m2 , median urine albumin:creatinine ratio [UACR] 111 mg/g), dapagliflozin did not change 24-hour sodium and volume excretion during 2 weeks of treatment. Dapagliflozin was associated with a modest increase in 24-hour glucose excretion on Day 4, which persisted at Day 14 and reversed to baseline after discontinuation. Mean 24-hour systolic BP decreased by -9.3 (95% confidence interval [CI] -19.1, 0.4) mmHg after 4 days and was sustained at Day 14 and at wash-out. Renin, angiotensin II, urinary aldosterone and copeptin levels increased from baseline. In DIAMOND (mean age 51 years, mean eGFR 59.0 mL/min/1.73 m2 , median UACR 608 mg/g), compared to placebo, dapagliflozin increased plasma renin (38.5 [95% CI 7.4, 78.8]%), aldosterone (19.1 [95% CI -5.9, 50.8]%), and copeptin levels (7.3 [95% CI 0.1, 14.5] pmol/L). CONCLUSIONS During a standardized sodium diet, dapagliflozin decreased BP but did not increase 24-hour sodium and volume excretion. The lack of increased natriuresis and diuresis may be attributed to activation of intra-renal compensatory mechanisms to prevent excessive water loss.
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Affiliation(s)
- Taha Sen
- Department of Clinical Pharmacy and PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Rosalie Scholtes
- Diabetes Centre, Department of Internal MedicineAmsterdam University Medical Centres, Location VU University Medical CenterAmsterdamThe Netherlands
| | - Peter J. Greasley
- Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&DAstraZenecaGothenburgSweden
| | - David Z. I. Cherney
- Division of Nephrology, Department of MedicineUniversity Health Network and University of TorontoTorontoOntarioCanada
| | - Claire C. J. Dekkers
- Department of Clinical Pharmacy and PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Marc Vervloet
- Department of Nephrology and Amsterdam Cardiovascular SciencesAmsterdam University Medical CenterAmsterdamThe Netherlands
| | - Alexander H. J. Danser
- Division of Pharmacology and Vascular Medicine, Department of Internal MedicineErasmus MCRotterdamThe Netherlands
| | - Sean J. Barbour
- Division of Nephrology, Department of MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Cecilia Karlsson
- Late‐stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&DAstraZenecaGothenburgSweden
| | - Ann Hammarstedt
- Late‐stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&DAstraZenecaGothenburgSweden
| | - Qiang Li
- The George Institute for Global HealthUNSW SydneySydneyNew South WalesAustralia
| | | | - Petter Bjornstad
- Department of Pediatrics, Division of EndocrinologyUniversity of Colorado School of MedicineAuroraColoradoUSA
- Department of Medicine, Division of NephrologyUniversity of Colorado School of MedicineAuroraColoradoUSA
| | - Daniel H. van Raalte
- Diabetes Centre, Department of Internal MedicineAmsterdam University Medical Centres, Location VU University Medical CenterAmsterdamThe Netherlands
| | - Hiddo J. L. Heerspink
- Department of Clinical Pharmacy and PharmacologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
- The George Institute for Global HealthUNSW SydneySydneyNew South WalesAustralia
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Scheen AJ. Counteracting heart failure with diabetes drugs: a review into the pharmacokinetic and pharmacodynamic properties. Expert Opin Drug Metab Toxicol 2022; 18:381-393. [PMID: 35876091 DOI: 10.1080/17425255.2022.2105693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION : Heart failure (HF) is becoming a huge public health burden. New diabetes drugs for type 2 diabetes (T2D), sodium-glucose cotransporter type 2 inhibitors (SGLT2is), reduce the rate of hospitalization for HF in placebo-controlled trials. AREAS COVERED : Pharmacokinetics of dapagliflozin and empagliflozin (in presence of renal impairment and hepatic dysfunction, two comorbidities frequently associated with HF) and pharmacodynamic studies in patients with HF. Main HF outcomes in T2D patients with cardiovascular risk and in patients with reduced (HFrEF) or preserved (HFpEF) ejection fraction, with or without T2D, from DAPA-HF, EMPEROR-Reduced and EMPEROR-Preserved original findings and post hoc analyses. EXPERT OPINION : No clinically relevant changes are expected concerning SGLT2i pharmacokinetics in patients with HF while pharmacodynamic studies reported improvements in myocardium/vascular parameters, biomarkers and functional status. All SGLT2is showed a remarkable reduction in hospitalization for HF in patients with T2D and high cardiovascular risk. Furthermore, both dapagliflozin and empagliflozin improved the prognosis of patients with HFrEF, independently of the presence of T2D. Similar results were reported with empagliflozin in patients with HFpEF, to be confirmed with dapagliflozin in an ongoing trial (DELIVER). Thus, SGLT2is offer a new opportunity for the prevention and management of HF in patients with or without T2D.
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Affiliation(s)
- André J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.,Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium
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van Ruiten CC, Hesp AC, van Raalte DH. Sodium glucose cotransporter-2 inhibitors protect the cardiorenal axis: Update on recent mechanistic insights related to kidney physiology. Eur J Intern Med 2022; 100:13-20. [PMID: 35414444 DOI: 10.1016/j.ejim.2022.03.031] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/23/2022] [Accepted: 03/29/2022] [Indexed: 12/11/2022]
Abstract
Sodium glucose cotransporter-2 (SGLT2) inhibitors have acquired a central role in the treatment of type 2 diabetes, chronic kidney disease including diabetic kidney disease, and heart failure with reduced ejection fraction. SGLT2 inhibitors lower glucose levels by inducing glycosuria. In addition, SGLT2 inhibitors improve cardiovascular outcomes (3-point MACE), end-stage kidney disease, hospitalization for heart failure, and cardiovascular mortality in people with and without diabetes. The mechanisms underlying these benefits have been extensively investigated, but remain poorly understood. In this review, we first summarize recent trial evidence and subsequently focus on (1) the mechanisms by which SGLT2 inhibitors improve kidney outcomes and (2) the potential role of the kidneys in mediating the cardioprotective effects of SGLT2 inhibitors.
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Affiliation(s)
- Charlotte C van Ruiten
- Amsterdam Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers (Amsterdam UMC), location VU University Medical Center, De Boelelaan 1117 (room ZH 4A63), Amsterdam 1081 HV, the Netherland.
| | - Anne C Hesp
- Amsterdam Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers (Amsterdam UMC), location VU University Medical Center, De Boelelaan 1117 (room ZH 4A63), Amsterdam 1081 HV, the Netherland
| | - Daniël H van Raalte
- Amsterdam Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers (Amsterdam UMC), location VU University Medical Center, De Boelelaan 1117 (room ZH 4A63), Amsterdam 1081 HV, the Netherland; Department of Vascular Medicine Amsterdam University Medical Center, Location VU University Medical Center, Amsterdam, the Netherland
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Maideen NMP, Balasubramanian R, Muthusamy S. A Comprehensive Review of the Pharmacologic Perspective on Loop Diuretic Drug Interactions with Therapeutically Used Drugs. Curr Drug Metab 2022; 23:188-199. [DOI: 10.2174/1389200223666220401092112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/16/2021] [Accepted: 01/18/2022] [Indexed: 11/22/2022]
Abstract
Background:
Loop diuretics help to manage the patients with edema associated with congestive heart failure, liver cirrhosis, and renal disease and hypertension. The patients taking loop diuretics may receive other medications to treat comorbidities leading to drug interactions.
Methodology:
The literature was searched in databases such as Medline/PMC/PubMed, Google Scholar, Cochrane Library, Science Direct, EMBASE, Web of science, Ebsco, Directory of open access journals (DOAJ) and reference lists to spot relevant articles using the keywords Drug interactions, Pharmacodynamic interactions, Loop diuretics, Bumetanide, Ethacrynic acid, Furosemide, and Torsemide.
Results:
Loop diuretics are associated with hypokalemia, ototoxicity and other adverse effects. The drugs affected by hypokalemia, and having the potential of inducing ototoxicity could interact with loop diuretics pharmacodynamically. Loop diuretics can interact with drugs such as amphotericin B, digoxin, angiotensin-converting enzyme inhibitors (ACE inhibitors), antidiabetic drugs, antifungal agents, dobutamine, gossypoland sotalol due to diuretic associated hypokalemia. In addition, the risk of ototoxicity could be enhanced by the concomitant use of loop diuretics and cisplatin, aminoglycoside antibiotics or phosphodiesterase 5 (PDE 5) inhibitors. Loop diuretics may also interact pharmacodynamically with drugs like cephalosporins, ceritinib, levothyroxine, pixantrone, probenecid, lithium, non-steroidal anti-inflammatory drugs (NSAIDs), sulfonylureas and herbal drugs.
Conclusion:
Clinicians, pharmacists and other health care providers should take responsibility for the safe use of medications. In addition, they are required to be aware of the drugs interacting with loop diuretics, to prevent adverse drug interactions.
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Affiliation(s)
| | - Rajkapoor Balasubramanian
- Department of Pharmacology, J.K.K. Nattraja College of Pharmacy, Komarapalayam- 638 183, Tamilnadu, India
| | - Sudha Muthusamy
- Department of Pharmacology, J.K.K. Nattraja College of Pharmacy, Komarapalayam- 638 183, Tamilnadu, India
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Mullens W, Martens P, Testani JM, Tang WHW, Skouri H, Verbrugge FH, Fudim M, Iacoviello M, Franke J, Flammer AJ, Palazzuoli A, Barragan PM, Thum T, Marcos MC, Miró Ò, Rossignol P, Metra M, Lassus J, Orso F, Jankowska EA, Chioncel O, Milicic D, Hill L, Seferovic P, Rosano G, Coats A, Damman K. Renal effects of guideline-directed medical therapies in heart failure: a consensus document from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2022; 24:603-619. [PMID: 35239201 DOI: 10.1002/ejhf.2471] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/22/2022] [Accepted: 03/01/2022] [Indexed: 11/11/2022] Open
Abstract
Novel pharmacologic treatment options reduce mortality and morbidity in a cost-effective manner in patients with heart failure (HF). Undisputedly, the effective implementation of these agents is an essential element of good clinical practice, which is endorsed by the European Society of Cardiology (ESC) guidelines on acute and chronic HF. Yet, physicians struggle to implement these therapies as they have to balance the true and/or perceived risks versus their substantial benefits in clinical practice. Any worsening of biomarkers of renal function is often perceived as being disadvantageous and is in clinical practice one of the most common reasons for ineffective drug implementation. However, even in this context, they clearly reduce mortality and morbidity in HF with reduced ejection fraction (HFrEF) patients, even in patients with poor renal function. Furthermore these agents are also beneficial in HF with mildly reduced ejection fraction (HFmrEF) and sodium-glucose cotransporter 2 (SGLT2) inhibitors more recently demonstrated a beneficial effect in HF with preserved ejection fraction (HFpEF). The emerge of several new classes (angiotensin receptor-neprilysin inhibitor [ARNI], SGLT2 inhibitors, vericiguat, omecamtiv mecarbil) and the recommendation by the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic HF of early initiation and titration of quadruple disease-modifying therapies (ARNI/angiotensin-converting enzyme inhibitor + beta-blocker + mineralocorticoid receptor antagonist and SGLT2 inhibitor) in HFrEF increases the likelihood of treatment-induced changes in renal function. This may be (incorrectly) perceived as deleterious, resulting in inertia of starting and uptitrating these lifesaving therapies. Therefore, the objective of this consensus document is to provide advice of the effect HF drugs on renal function.
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Affiliation(s)
- Wilfried Mullens
- Ziekenhuis Oost Limburg, Genk, University Hasselt, Hasselt, Belgium
| | - Pieter Martens
- Ziekenhuis Oost Limburg, Genk, University Hasselt, Hasselt, Belgium
- Cleveland Clinic, Cleveland, OH, USA
| | | | | | - Hadi Skouri
- American University of Beirut Medical Center-Beirut, Beirut, Lebanon
| | - Frederik H Verbrugge
- Centre for Cardiovascular Diseases, University Hospital Brussel, Jette, Belgium
- Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
- Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium
| | - Marat Fudim
- Duke University Medical Center, Durham, NC, USA
- Duke Clinical Research Institute, Durham, NC, USA
| | - Massimo Iacoviello
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | | | - Andreas J Flammer
- University Heart Center, University Hospital Zurich, Zurich, Switzerland
| | - Alberto Palazzuoli
- Cardiovascular Diseases Unit, Department of Medical Sciences, Le Scotte Hospital Siena, Siena, Italy
- School of Nursing and Midwifery, Queen's University, Belfast, UK
| | | | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
- Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany
| | - Marta Cobo Marcos
- Hospital Universitario Puerta de Hierro Majadahonda, CIBERCV, Madrid, Spain
| | - Òscar Miró
- Emergency Department, Hospital Clínic, Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Patrick Rossignol
- Université de Lorraine, Inserm 1433 CIC-P CHRU de Nancy, Inserm U1116, and F-CRIN INI-CRCT, Nancy, France
| | | | - Johan Lassus
- Heart and Lung Center, Cardiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | | | - Ewa A Jankowska
- Institute of Heart Diseases, Wroclaw Medical University and Institute of Heart Diseases, University Hospital in Wroclaw, Wroclaw, Poland
| | - Ovidiu Chioncel
- Emergency Institute for Cardiovascular Diseases 'Prof. C.C. Iliescu', University of Medicine Carol Davila, Bucharest, Romania
| | - Davor Milicic
- Department of Cardiovascular Diseases, University of Zagreb School of Medicine & University Hospital Centre Zagreb, Zagreb, Croatia
| | - Loreena Hill
- School of Nursing & Midwifery, Queen's University, Belfast, UK
| | - Petar Seferovic
- Universi Faculty of Medicine, University of Belgrade, and Serbian Academy of Arts and Sciences, Belgrade, Serbia
| | | | | | - Kevin Damman
- University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Zhou J, Lee S, Leung KSK, Wai AKC, Liu T, Liu Y, Chang D, Wong WT, Wong ICK, Cheung BMY, Zhang Q, Tse G. Incident heart failure and myocardial infarction in sodium-glucose cotransporter-2 vs. dipeptidyl peptidase-4 inhibitor users. ESC Heart Fail 2022; 9:1388-1399. [PMID: 35132823 PMCID: PMC8934922 DOI: 10.1002/ehf2.13830] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 01/16/2022] [Indexed: 12/22/2022] Open
Abstract
AIMS This study aimed to compare the rates of major cardiovascular adverse events in sodium-glucose cotransporter-2 inhibitors (SGLT2I) and dipeptidyl peptidase-4 inhibitors (DPP4I) users in a Chinese population. SGLT2I and DPP4I are increasingly prescribed for type 2 diabetes mellitus patients. However, few population-based studies are comparing their effects on incident heart failure or myocardial infarction. METHODS AND RESULTS This was a population-based retrospective cohort study using the electronic health record database in Hong Kong, including type 2 diabetes mellitus patients receiving either SGLT2I or DPP4I from 1 January 2015 to 31 December 2020. Propensity score matching was performed in a 1:1 ratio based on demographics, past comorbidities, and non-SGLT2I/DPP4I medications with nearest neighbour matching (caliper = 0.1). Univariable and multivariable Cox models were used to identify significant predictors for new-onset heart failure, new-onset myocardial infarction, cardiovascular mortality, and all-cause mortality. Sensitivity analyses with competing risk models and multiple propensity score matching approaches were conducted. A total of 41 994 patients (58.89% males, median admission age at 58 years old, interquartile range [IQR]: 51.2-65.3) were included with a median follow-up of 5.6 years (IQR: 5.32-5.82). In the matched cohort, SGLT2I use was significantly associated with lower risks of new-onset heart failure (hazard ratio [HR]: 0.73, 95% confidence interval [CI]: [0.66, 0.81], P < 0.0001), myocardial infarction (HR: 0.81, 95% CI: [0.73, 0.90], P < 0.0001), cardiovascular mortality (HR: 0.67, 95% CI: [0.53, 0.84], P < 0.001), and all-cause mortality (HR: 0.26, 95% CI: [0.24, 0.29], P < 0.0001) after adjusting for significant demographics, past comorbidities, and non-SGLT2I/DPP4I medications. CONCLUSIONS SGLT2 inhibitors are protective against adverse cardiovascular events including new-onset heart failure, myocardial infarction, cardiovascular mortality, and all-cause mortality. The prescription of SGLT2I is preferred when taken into consideration individual cardiovascular and metabolic risk profiles in addition to drug-drug interactions.
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Affiliation(s)
- Jiandong Zhou
- Nuffield Department of MedicineUniversity of OxfordOxfordUK
| | - Sharen Lee
- Diabetes Research UnitCardiovascular Analytics GroupHong KongChina
| | - Keith Sai Kit Leung
- Emergency Medicine Unit, Faculty of MedicineThe University of Hong KongHong KongChina
| | - Abraham Ka Chung Wai
- Emergency Medicine Unit, Faculty of MedicineThe University of Hong KongHong KongChina
| | - Tong Liu
- Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of CardiologySecond Hospital of Tianjin Medical UniversityTianjinChina
| | - Ying Liu
- Department of CardiologyThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Dong Chang
- Xiamen Cardiovascular HospitalXiamen UniversityXiamenChina
| | - Wing Tak Wong
- School of Life Sciences, State Key Laboratory of Agrobiotechnology (CUHK)The Chinese University of Hong KongHong KongChina
| | - Ian Chi Kei Wong
- Department of Pharmacology and PharmacyUniversity of Hong KongHong KongChina
| | - Bernard Man Yung Cheung
- Division of Clinical Pharmacology and Therapeutics, Department of MedicineThe University of Hong KongHong KongChina
| | - Qingpeng Zhang
- School of Data ScienceCity University of Hong KongHong KongChina
| | - Gary Tse
- Diabetes Research UnitCardiovascular Analytics GroupHong KongChina
- Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of CardiologySecond Hospital of Tianjin Medical UniversityTianjinChina
- Department of CardiologyThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
- Kent and Medway Medical SchoolCanterburyKentUK
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Tang J, Ye L, Yan Q, Zhang X, Wang L. Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Water and Sodium Metabolism. Front Pharmacol 2022; 13:800490. [PMID: 35281930 PMCID: PMC8905496 DOI: 10.3389/fphar.2022.800490] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 01/24/2022] [Indexed: 12/19/2022] Open
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert hypoglycemic and diuretic effects by inhibiting the absorption of sodium and glucose from the proximal tubule. Currently available data indicate that SGLT2 inhibitors transiently enhance urinary sodium excretion and urinary volume. When combined with loop diuretics, SGLT2 inhibitors exert a synergistic natriuretic effect. The favorable diuretic profile of SGLT2 inhibitors may confer benefits to volume management in patients with heart failure but this natriuretic effect may not be the dominant mechanism for the superior long-term outcomes observed with these agents in patients with heart failure. The first part of this review explores the causes of transient natriuresis and the diuretic mechanisms of SGLT2 inhibitors. The second part provides an overview of the synergistic effects of combining SGLT2 inhibitors with loop diuretics, and the third part summarizes the mechanisms of cardiovascular protection associated with the diuretic effects of SGLT2 inhibitors.
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Affiliation(s)
- Jun Tang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Lifang Ye
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Qiqi Yan
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Xin Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Lihong Wang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.,Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
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Yang L, Gabriel N, Hernandez I, Vouri SM, Kimmel SE, Bian J, Guo J. Identifying Patients at Risk of Acute Kidney Injury Among Medicare Beneficiaries With Type 2 Diabetes Initiating SGLT2 Inhibitors: A Machine Learning Approach. Front Pharmacol 2022; 13:834743. [PMID: 35359843 PMCID: PMC8961669 DOI: 10.3389/fphar.2022.834743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 01/20/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction: To predict acute kidney injury (AKI) risk in patients with type 2 diabetes (T2D) prescribed sodium-glucose cotransporter two inhibitors (SGLT2i). Methods: Using a 5% random sample of Medicare claims data, we identified 17,694 patients who filled ≥1 prescriptions for canagliflozin, dapagliflozin and empagliflozin in 2013–2016. The cohort was split randomly and equally into training and testing sets. We measured 65 predictor candidates using claims data from the year prior to SGLT2i initiation. We then applied three machine learning models, including random forests (RF), elastic net and least absolute shrinkage and selection operator (LASSO) for risk prediction. Results: The incidence rate of AKI was 1.1% over a median 1.5 year follow up. Among three machine learning methods, RF produced the best prediction (C-statistic = 0.72), followed by LASSO and elastic net (both C-statistics = 0.69). Among individuals classified in the top 10% of the RF risk score (i.e., high risk group), the actual incidence rate of AKI was as high as 3.7%. In the logistic regression model including 14 important risk factors selected by LASSO, use of loop diuretics [adjusted odds ratio (95% confidence interval): 3.72 (2.44–5.76)] had the strongest association with AKI incidence. Disscusion: Our machine learning model efficiently identified patients at risk of AKI among Medicare beneficiaries with T2D undergoing SGLT2i treatment.
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Affiliation(s)
- Lanting Yang
- Department of Pharmacy and Therapeutics, University of Pittsburgh, Pittsburgh, PA, United States
| | - Nico Gabriel
- Division of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, CA, United States
| | - Inmaculada Hernandez
- Division of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, CA, United States
| | - Scott M. Vouri
- Department of Pharmaceutical Outcomes and Policy, University of Florida, Gainesville, FL, United States
| | - Stephen E. Kimmel
- Department of Epidemiology, University of Florida, Gainesville, FL, United States
| | - Jiang Bian
- Department of Health Outcomes and Biomedical Informatics, University of Florida, Gainesville, FL, United States
| | - Jingchuan Guo
- Department of Pharmaceutical Outcomes and Policy, University of Florida, Gainesville, FL, United States
- *Correspondence: Jingchuan Guo,
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Scholtes RA, Muskiet MH, van Baar MJ, Hesp AC, Greasley PJ, Hammarstedt A, Karlsson C, Hallow KM, Danser AJ, Heerspink HJ, van Raalte DH. The adaptive renal response for volume homeostasis during two weeks of dapagliflozin treatment in people with type 2 diabetes and preserved renal function on a sodium-controlled diet. Kidney Int Rep 2022; 7:1084-1092. [PMID: 35570989 PMCID: PMC9091605 DOI: 10.1016/j.ekir.2022.02.023] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/11/2022] [Accepted: 02/15/2022] [Indexed: 12/20/2022] Open
Abstract
Introduction Proximal tubule sodium uptake is diminished following sodium glucose cotransporter 2 (SGLT2) inhibition. We previously showed that during SGLT2 inhibition, the kidneys adapt by increasing sodium uptake at distal tubular segments, thereby maintaining body sodium balance. Despite continuous glycosuria, we detected no increased urine volumes. We therefore assessed the adaptive renal responses to prevent excessive fluid loss. Methods We conducted a mechanistic open-label study in people with type 2 diabetes mellitus with preserved kidney function, who received a standardized sodium intake (150 mmol/d) to evaluate the effects of dapagliflozin on renin-angiotensin-aldosterone system (RAAS) hormones, volume-related biomarkers, urinary albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR), at start of treatment (day 4), end of treatment (day 14), and follow-up (day 18). Results A total of 14 people were enrolled. Plasma renin and angiotensin II and urinary aldosterone and angiotensinogen were acutely and persistently increased during treatment with dapagliflozin. Plasma copeptin level was numerically increased after 4 days (21%). Similarly, fractional urea excretion was significantly decreased at start of treatment (−17%). Free water clearance was significantly decreased after 4 days (−74%) and 14 days (−41%). All changes reversed after dapagliflozin discontinuation. Conclusion Dapagliflozin-induced osmotic diuresis triggers kidney adaptive mechanisms to maintain volume and sodium balance in people with type 2 diabetes and preserved kidney function. ClinicalTrials.gov (identification: NCT03152084).
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Ng HY, Leung FF, Kuo WH, Lee WC, Lee CT. Dapagliflozin and xanthine oxidase inhibitors improve insulin resistance and modulate renal glucose and urate transport in metabolic syndrome. Clin Exp Pharmacol Physiol 2021; 48:1603-1612. [PMID: 34407232 DOI: 10.1111/1440-1681.13574] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 08/15/2021] [Accepted: 08/16/2021] [Indexed: 11/28/2022]
Abstract
Disturbance in glucose and uric acid metabolism is the major disorder of metabolic syndrome (MetS). The kidneys play an important role in the management of glucose and uric acid. The aim of our study was to investigate alterations in renal glucose and uric acid transporters in animals with MetS after treatment with dapagliflozin and xanthine oxidase inhibitors (allopurinol and febuxostat). Sprague-Dawley rats were fed normal chow or a high fructose diet for the first 3 months. The fructose-fed animals were then treated with dapagliflozin, allopurinol, febuxostat, or no treatment for the next 3 months. Fasting glucose, insulin resistance, and hyperuricaemia were improved in all treatment groups except that in the fructose group (all p < 0.05). Both allopurinol and febuxostat reversed the increase in levels of sodium glucose cotransporter (SGLT) 1, SGLT2, and glucose transporter (GLUT) 2 (all p < 0.05). Dapagliflozin alleviated hyperuricaemia and induced uricosuria without affecting serum xanthine oxidase activity. Dapagliflozin suppressed the expression of GLUT9, urate transporter, and urate anion exchanger 1 (all p < 0.05), which was similar to the effects of allopurinol and febuxostat. The results suggest that treatment with dapagliflozin and xanthine oxidase inhibitors improved insulin resistance and reversed the increased expression of glucose and urate transporters in the kidney.
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Affiliation(s)
- Hwee-Yeong Ng
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Foong-Fah Leung
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Wei-Hung Kuo
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Wen-Chin Lee
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Te Lee
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Omar M, Jensen J, Burkhoff D, Frederiksen PH, Kistorp C, Videbæk L, Poulsen MK, Gustafsson F, Køber L, Borlaug BA, Schou M, Møller JE. Effect of Empagliflozin on Blood Volume Redistribution in Patients With Chronic Heart Failure and Reduced Ejection Fraction: An Analysis from the Empire HF Randomized Clinical Trial. Circ Heart Fail 2021; 15:e009156. [PMID: 34743533 DOI: 10.1161/circheartfailure.121.009156] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Background: Stressed blood volume (SBV) is a major determinant of systemic and pulmonary venous pressures which, in turn, determine left and right ventricular fillings and regulates cardiac output via the Frank-Starling mechanism. It is not known whether inhibition of the sodium-glucose cotransporter-2 (SGLT2) favorably affects SBV. We investigated the effect of empagliflozin on estimated stressed blood volume (eSBV) in patients with heart failure andreduced ejection fraction (HFrEF) compared to placebo. Methods: This was a post-hoc analysis of an investigator-initiated, double-blinded, placebo controlled, randomized trial. Seventy patients were assigned to empagliflozin 10 mg or matching placebo once-daily for 12 weeks. Patients underwent right heart catheterization at rest and during exercise at baseline and follow-up. The outcome was change in eSBV after 12 weeks of empagliflozin treatment over the full range of exercise, determined using a recently introduced analytical approach based on invasive hemodynamic assessment. Results: Patients with HFrEF, mean age, 57 years and mean ejection fraction 27 %, with 47 patients (71%) receiving diuretics were randomized. The effect of empagliflozin on eSBV over the full range of exercise loads showed a statistically significant reduction compared with placebo (-198.4 mL, 95%CI: -317.4; -79.3, p=0.001), a 9% decrease. The decrease in eSBV by empagliflozin was significantly correlated with the decrease in PCWP ((R= ̶ 0.33, p<0.0001). The effect of empagliflozin was consistent across subgroup analysis. Conclusions: Empagliflozin treatment significantly reduced stressed blood volume compared with placebo after 12 weeks of treatment in patients with stable chronic HFrEF during sub maximal exercise. Registration: URL: https://www.clinicaltrials.gov, Unique identifier: NCT03198585.
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Affiliation(s)
- Massar Omar
- Department of Cardiology, Odense University Hospital, J. B. Winsløws Vej 4, 5000 Odense C, Denmark; Steno Diabetes Center Odense, 5000 Odense C, Denmark; Faculty of Health Sciences, University of Southern Denmark, J.B. Winsløws Vej 19, 3, 5000 Odense C, Denmark
| | - Jesper Jensen
- Department of Cardiology, Herlev and Gentofte University Hospital, Borgmester Ib Juuls Vej 1, 2730 Herlev Denmark; Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | | | - Peter H Frederiksen
- Department of Cardiology, Odense University Hospital, J. B. Winsløws Vej 4, 5000 Odense C, Denmark; Faculty of Health Sciences, University of Southern Denmark, J.B. Winsløws Vej 19, 3, 5000 Odense C, Denmark
| | - Caroline Kistorp
- Department of Endocrinology, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 København Ã, Denmark; Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Lars Videbæk
- Department of Cardiology, Odense University Hospital, J. B. Winsløws Vej 4, 5000 Odense C, Denmark
| | - Mikael Kjær Poulsen
- Department of Cardiology, Odense University Hospital, J. B. Winsløws Vej 4, 5000 Odense C, Denmark
| | - Finn Gustafsson
- Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Lars Køber
- Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Barry A Borlaug
- Division of Cardiovascular Diseases, Department of Cardiovascular Medicine, Mayo Clinic Hospital, Rochester, MN
| | - Morten Schou
- Department of Cardiology, Herlev and Gentofte University Hospital, Borgmester Ib Juuls Vej 1, 2730 Herlev Denmark; Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Jacob Eifer Møller
- Department of Cardiology, Odense University Hospital, J. B. Winsløws Vej 4, 5000 Odense C, Denmark; Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Faculty of Health Sciences, University of Southern Denmark, J.B. Winsløws Vej 19, 3, 5000 Odense C, Denmark
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48
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Inpatient Diuretic Management of Acute Heart Failure: A Practical Review. Am J Cardiovasc Drugs 2021; 21:595-608. [PMID: 33709346 DOI: 10.1007/s40256-020-00463-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/10/2020] [Indexed: 02/08/2023]
Abstract
The inpatient treatment of acute heart failure (AHF) is aimed at achieving euvolemia, relieving symptoms, and reducing rehospitalization. Adequate treatment of AHF is rooted in understanding the pharmacokinetics and pharmacodynamics of select diuretic agents used to achieve decongestion. While loop diuretics remain the primary treatment of AHF, the dosing strategies of loop diuretics and the use of adjunct diuretic classes to augment clinical response can be complex. This review examines the latest strategies for diuretic management in patients with AHF, including dosing and monitoring strategies, interaction of diuretics with other medication classes, use adjunctive therapies, and assessing endpoints for diuretic. The goal of the review is to guide the reader through commonly encountered clinical scenarios and pitfalls in the diuretic management of patients with AHF.
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49
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Chang DY, Li XQ, Chen M, Zhao MH. Dapagliflozin Ameliorates Diabetic Kidney Disease via Upregulating Crry and Alleviating Complement Over-activation in db/db Mice. Front Pharmacol 2021; 12:729334. [PMID: 34712135 PMCID: PMC8546210 DOI: 10.3389/fphar.2021.729334] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 09/29/2021] [Indexed: 12/30/2022] Open
Abstract
Sodium-glucose cotransporter 2(SGLT2) inhibitors show prominent renal protective effect in diabetic kidney disease (DKD), anti-inflammatory effect being one of its key mechanisms. Over-activation of the complement system, a crucial part of innate immunity, plays an important role in DKD. We aimed to investigate the effect of SGLT2 inhibitors on alleviating complement over-activation in DKD. Db/db mice were randomly divided into two groups, with 7 mice in each group treated with dapagliflozin and vehicle respectively, and 7 mice in m/m mice group. Laboratory and renal pathological parameters were evaluated. Mouse proximal tubular epithelial cells (MPTECs) were cultured and treated with high glucose. Dapagliflozin and dimethyloxallyl glycine (DMOG) were added as conditional treatment. Dapagliflozin-treated db/db mice showed significantly lower urinary albumin than vehicle-treated ones. Besides typical glomerular and tubulointerstitial injury, both C3b and membrane attack complex (MAC) depositions were significantly attenuated in dapagliflozin-treated db/db mice. The expression of complement receptor type 1-related protein y (Crry), a key complement regulator which inhibits complement over-activation, was significantly upregulated by dapagliflozin. Dapagliflozin-mediated Crry upregulation was associated with inhibition of HIF-1α accumulation under high glucose. When HIF-1α expression was stabilized by DMOG, the protective effect of dapagliflozin via upregulating Crry was blocked. In conclusion, dapagliflozin could attenuate complement over-activation in diabetic mice via upregulating Crry, which is associated with the suppression of HIF-1α accumulation in MPTECs.
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Affiliation(s)
- Dong-Yuan Chang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao-Qian Li
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Min Chen
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Ming-Hui Zhao
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
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50
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Natali A, Nesti L, Tricò D, Ferrannini E. Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: a narrative review of clinical evidence. Cardiovasc Diabetol 2021; 20:196. [PMID: 34583699 PMCID: PMC8479881 DOI: 10.1186/s12933-021-01385-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 09/17/2021] [Indexed: 02/08/2023] Open
Abstract
The impressive results of recent clinical trials with glucagon-like peptide-1 receptor agonists (GLP-1Ra) and sodium glucose transporter 2 inhibitors (SGLT-2i) in terms of cardiovascular protection prompted a huge interest in these agents for heart failure (HF) prevention and treatment. While both classes show positive effects on composite cardiovascular endpoints (i.e. 3P MACE), their actions on the cardiac function and structure, as well as on volume regulation, and their impact on HF-related events have not been systematically evaluated and compared. In this narrative review, we summarize and critically interpret the available evidence emerging from clinical studies. While chronic exposure to GLP-1Ra appears to be essentially neutral on both systolic and diastolic function, irrespective of left ventricular ejection fraction (LVEF), a beneficial impact of SGLT-2i is consistently detectable for both systolic and diastolic function parameters in subjects with diabetes with and without HF, with a gradient proportional to the severity of baseline dysfunction. SGLT-2i have a clinically significant impact in terms of HF hospitalization prevention in subjects at high and very high cardiovascular risk both with and without type 2 diabetes (T2D) or HF, while GLP-1Ra have been proven to be safe (and marginally beneficial) in subjects with T2D without HF. We suggest that the role of the kidney is crucial for the effect of SGLT-2i on the clinical outcomes not only because these drugs slow-down the time-dependent decline of kidney function and enhance the response to diuretics, but also because they attenuate the meal-related anti-natriuretic pressure (lowering postprandial hyperglycemia and hyperinsulinemia and preventing proximal sodium reabsorption), which would reduce the individual sensitivity to day-to-day variations in dietary sodium intake.
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Affiliation(s)
- Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56100, Pisa, Italy.
| | - Lorenzo Nesti
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56100, Pisa, Italy
| | - Domenico Tricò
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56100, Pisa, Italy
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
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