Metabolic Communication by SGLT2 Inhibition

Circulation, Journal Year: 2023, Volume and Issue: 149(11), P. 860 - 884

Published: Dec. 28, 2023

BACKGROUND: SGLT2 (sodium-glucose cotransporter 2) inhibitors (SGLT2i) can protect the kidneys and heart, but underlying mechanism remains poorly understood. METHODS: To gain insights on primary effects of SGLT2i that are not confounded by pathophysiologic processes or secondary to improvement SGLT2i, we performed an in-depth proteomics, phosphoproteomics, metabolomics analysis integrating signatures from multiple metabolic organs body fluids after 1 week treatment nondiabetic as well diabetic mice with early uncomplicated hyperglycemia. RESULTS: Kidneys reacted most strongly in terms proteomic reconfiguration, including evidence for less proximal tubule glucotoxicity a broad downregulation apical uptake transport machinery (including sodium, glucose, urate, purine bases, amino acids), supported mouse human interactome studies. affected heart liver signaling, more reactive included white adipose tissue, showing lipolysis, and, particularly, gut microbiome, lower relative abundance bacteria taxa capable fermenting phenylalanine tryptophan cardiovascular uremic toxins, resulting plasma levels these compounds p-cresol sulfate). was detectable murine stool samples its addition microbiota fermentation recapitulated some microbiome findings, suggesting direct inhibition aromatic acids tryptophan. In lacking patients decompensated failure diabetes, likewise reduced circulating sulfate, impaired contractility rhythm induced pluripotent stem cell–derived engineered tissue. CONCLUSIONS: formation toxins such sulfate thereby their exposure need renal detoxification, which, combined kidney transporters acid, urate uptake), provides foundation protection.

Language: Английский

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Sodium-glucose cotransporter-2 inhibitors and their potential role in dementia onset and cognitive function in patients with diabetes mellitus: a systematic review and meta-analysis

Frontiers in Neuroendocrinology, Journal Year: 2024, Volume and Issue: 73, P. 101131 - 101131

Published: Feb. 16, 2024

This systematic review and meta-analysis aimed to determine the association between use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors dementia onset as well cognitive function in patients with diabetes mellitus. We comprehensively searched MEDLINE, Embase, CENTRAL databases select relevant studies published up August 2023. The SGLT-2 significantly lowers risk compared SGLT-2i non-users (Hazard ratio: 0.68, 95 % CI: 0.50-0.92). Furthermore, our findings indicated a positive effect inhibitor on score improvement, demonstrated by standardized mean difference 0.88 (95 0.32-1.44), particularly among populations mild impairment or dementia. indicate potential role reducing These underscore need for well-controlled large clinical trials future research this field.

Language: Английский

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SGLT2 inhibitors for prevention and management of cancer treatment-related cardiovascular toxicity: a review of potential mechanisms and clinical insights

Cardio-Oncology, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 11, 2025

Abstract More evidence-based strategies are needed for preventing and managing cancer treatment-related cardiovascular toxicity (CTR-CVT). Owing to the growing body of evidence supporting their cardioprotective role in several cardiac injury scenarios, sodium-glucose cotransporter 2 inhibitors (SGLT2i) may be beneficial treating CTR-CVT. In October 2024, a search was conducted PubMed database review full studies investigating SGLT2i against We identified 44 published/pre-print 3 ongoing randomised controlled trial across eight types treatment (anthracyclines, platinum-containing therapy, immune checkpoint inhibitors, HER2-targeted therapies, kinase androgen deprivation multiple myeloma therapies 5-fluorouracil). Most used animal models focussed on primary prevention. 43 found some effect CTR-CVT, which cases included ejection fraction decline aberrations electrophysiological parameters. Some also observed effects mortality. A central triad anti-inflammatory, anti-oxidative anti-apoptotic mechanisms likely underlie SGLT2i-mediated cardioprotection Overall, this research suggests that promising candidate CTR-CVT either as monotherapy or combination with other drugs. However, literature is limited no prospective trials prevention management exist most existing human retrospective data based diabetic populations. Future work must focus addressing these limitations current literature.

Language: Английский

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The Role of SGLT2-Inhibitors Across All Stages of Heart Failure and Mechanisms of Early Clinical Benefit: From Prevention to Advanced Heart Failure

Biomedicines, Journal Year: 2025, Volume and Issue: 13(3), P. 608 - 608

Published: March 3, 2025

Sodium-glucose cotransporter-2 inhibitors (SGLT2i), initially developed as antihyperglycemic agents, have revolutionized heart failure (HF) management, offering substantial benefits across all stages and phenotypes of the disease. Regardless left ventricular ejection fraction (LVEF), these agents proven efficacy in both chronic acute HF presentations. This review explores SGLT2i applications spanning continuum, from early (Stage A) at-risk individuals to mitigation progression advanced D). Evidence numerous trials has shown that significantly lower rates hospitalization, improve renal function, decreases cardiovascular mortality, highlighting their multifaced mechanisms action care. also highlights potential by which exert beneficial effects on systems, each contributing sustained clinical improvements. However, integration into guideline-directed medical therapy poses practical challenges, including initiation timing, dosing, monitoring, are addressed support effective treatment adaptation patient populations. Ultimately, this provides a comprehensive assessment foundational HF, emphasizing role an intervention multiple aimed at improving outcomes entire spectrum.

Language: Английский

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Cardiovascular therapeutic targets of sodium-glucose co-transporter 2 (SGLT2) inhibitors beyond heart failure

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: 270, P. 108861 - 108861

Published: April 15, 2025

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are oral antidiabetic agents that have shown significant improvements in cardiovascular and renal outcomes among patients with heart failure (HF), regardless of diabetic status, establishing them as a cornerstone therapy. In addition to glycemic control the osmotic diuretic effect, inhibition SGLT2 improves endothelial function vasodilation, optimizing myocardial energy metabolism preserving cardiac contractility. Moreover, may exhibit anti-inflammatory properties attenuate acute ischemia/reperfusion injury, thereby reducing infarct size, enhancing left ventricular function, mitigating arrhythmias. These pleiotropic effects demonstrated efficacy across various conditions, ranging from chronic coronary syndromes extending arrhythmias, valvular disease, cardiomyopathies, cardio-oncology, cerebrovascular disease. This review provides an overview current literature on potential mechanisms underlying effectiveness wide range diseases beyond HF.

Language: Английский

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Empagliflozin attenuates trastuzumab-induced cardiotoxicity through suppression of DNA damage and ferroptosis

Life Sciences, Journal Year: 2022, Volume and Issue: 312, P. 121207 - 121207

Published: Nov. 17, 2022

Language: Английский

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GLP-1 Receptor Agonist Therapy With and Without SGLT2 Inhibitors in Patients With Type 2 Diabetes

Journal of the American College of Cardiology, Journal Year: 2023, Volume and Issue: 82(6), P. 517 - 525

Published: July 31, 2023

Language: Английский

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Ketones and the cardiovascular system

Nature Cardiovascular Research, Journal Year: 2023, Volume and Issue: 2(5), P. 425 - 437

Published: April 10, 2023

Language: Английский

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Molecular Mechanisms and Therapeutic Implications of Endothelial Dysfunction in Patients with Heart Failure

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(5), P. 4321 - 4321

Published: Feb. 21, 2023

Heart failure is a complex medical syndrome that attributed to number of risk factors; nevertheless, its clinical presentation quite similar among the different etiologies. displays rapidly increasing prevalence due aging population and success treatment devices. The pathophysiology heart comprises several mechanisms, such as activation neurohormonal systems, oxidative stress, dysfunctional calcium handling, impaired energy utilization, mitochondrial dysfunction, inflammation, which are also implicated in development endothelial dysfunction. with reduced ejection fraction usually result myocardial loss, progressively ends remodeling. On other hand, preserved common patients comorbidities diabetes mellitus, obesity, hypertension, trigger creation micro-environment chronic, ongoing inflammation. Interestingly, dysfunction both peripheral vessels coronary epicardial microcirculation characteristic categories has been associated worse cardiovascular outcomes. Indeed, exercise training drug display favorable effects against apart from their established direct benefit.

Language: Английский

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Optimisation of treatments for heart failure with reduced ejection fraction in routine practice: a position statement from a panel of experts

Revista Española de Cardiología (English Edition), Journal Year: 2023, Volume and Issue: 76(10), P. 813 - 820

Published: March 11, 2023

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