Gliflozines use in heart failure patients. Focus on renal actions and overview of clinical experience

Use of type 2 sodium-glucose cotransporter inhibitors (SGLT2i) gliflozines have first been applied to treatment of diabetic patients. In this setting, unexpected benefits on concomitant heart failure (HF) were seen in large trials. This clinical benefit was initially traced back to their natriuretic properties and as such they were also included in the therapeutic armamentarium of HF treatment. However, further insight into their mechanism of action has clarified their complex interaction with kidney function which better explains their prompt effectiveness in ameliorating HF outcome in the long-term, independent of left ventricular ejection fraction (LVEF) phenotype and concomitant presence of diabetes and/or chronic renal disease. This mainly results from the ability of SGLT2i to counteract the HF-associated hyperactivity of the sympathetic system and neurohormonal activation by modifying the pattern of renal tubular sodium and glucose reabsorption which results in curbing the overall sodium reabsorption. Their action results in decreased kidney workload and related oxygen consumption thus indirectly reducing sympathetic activity. The complex renal functional changes associated with HF and their modifications during SGLT2i administration will be reviewed

Quali soluzioni future per la dialisi peritoneale?

La dialisi peritoneale è una efficace tecnica sostitutiva della funzione renale nel paziente uremico, tuttavia è generalmente sotto-utilizzata. Ciò è almeno in parte attribuibile agli effetti sfavorevoli su integrità e funzione peritoneale (bioincompatibilità) delle attuali soluzioni a base di glucosio. L’uso delle soluzioni standard può indurre nel peritoneo diverse alterazioni quali infiammazione, transizione mesotelio-mesemchima e neoangiogenesi. Lo stadio finale è rappresentato dalla fibrosi, che causa una riduzione della capacità di filtrazione peritoneale che può arrivare alla completa insufficienza ultrafiltrativa con necessità di passare all’emodialisi. Oltre che locale (peritoneo) la bioincompatibilità può anche essere sistemica per l’eccessivo assorbimento di glucosio presente nel dialisato. Diverse strategie sono state impiegate per migliorare la biocompatibilità delle soluzioni per dialisi peritoneale, sulla base dei suggeriti fattori causali. Le soluzioni disponibili in commercio alternative alle standard includono quelle con bassi livelli di prodotti di degradazione del glucosio e pH neutro e quelle con icodestrina o aminoacidi. Tali soluzioni possono offrire alcuni benefici clinici ma hanno alcune limitazioni e la loro biocompatibilità è oggetto di discussione. Strategie più recenti includono l’uso nel dialisato di agenti citoprotettivi o di agenti osmo-metabolici. In questo lavoro vengono presi in esame i diversi approcci allo sviluppo di nuove soluzioni per dialisi peritoneale, atti a migliorare l’outcome clinico del paziente e la sopravvivenza della tecnica, di possibile impiego in un futuro auspicabilmente prossimo

Effect of peritoneal dialysis fluid containing osmo-metabolic agents on human endothelial cells

Background: The use of glucose as the only osmotic agent in peritoneal dialysis (PD) solutions (PDSs) is believed to exert local (peritoneal) and systemic detrimental actions, particularly in diabetic PD patients. To improve peritoneal biocompatibility, we have developed more biocompatible PDSs containing xylitol and carnitine along with significantly less amounts of glucose and have tested them in cultured Human Vein Endothelial Cells (HUVECs) obtained from the umbilical cords of healthy (C) and gestational diabetic (GD) mothers. Methods: Primary C- and GD-HUVECs were treated for 72 hours with our PDSs (xylitol 0.7% and 1.5%, whereas carnitine and glucose were fixed at 0.02% and 0.5%, respectively) and two glucose-based PDSs (glucose 1.36% or 2.27%). We examined their effects on endothelial cell proliferation (cell count), viability (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay), intracellular nitro-oxidative stress (peroxynitrite levels), Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 membrane exposure (flow cytometry), and HUVEC-monocyte interactions (U937 adhesion assay). Results: Compared to glucose-based PDSs, our in vitro studies demonstrated that the tested PDSs did not change the proliferative potential both in C- and GD-HUVECs. Moreover, our PDSs significantly improved endothelial cell viability, compared to glucose-based PDSs and basal condition. Notably, glucose-based PDSs significantly increased the intracellular peroxynitrite levels, Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 membrane exposure, and endothelial cell-monocyte interactions in both C- and GD-HUVECs, as compared with our experimental PDSs. Conclusion: Present results show that in control and diabetic human endothelial cell models, xylitol-carnitine-based PDSs do not cause cytotoxicity, nitro-oxidative stress, and inflammation as caused by hypertonic glucose-based PDSs. Since xylitol and carnitine are also known to favorably affect glucose homeostasis, these findings suggest that our PDSs may represent a desirable hypertonic solution even for diabetic patients in PD

Sweeteners: erythritol, xylitol and cardiovascular risk - friend or foe?

Hyperglycemia harms vascular health and promotes platelet aggregation. Reducing glucose concentration is crucial, and sugar alcohols may aid this effort. Used for over 50 years in food, cosmetic, and pharmaceutical industries, erythritol and xylitol minimally affect plasma glucose and insulin levels while promoting the release of beneficial gastrointestinal hormones such as e.g. glucagon-like peptide-1 (GLP-1). These properties make them particularly appealing for individuals with diabetes, obesity, and metabolic syndrome. Recent pilot trials suggest that xylitol and erythritol might temporarily alter platelet aggregation. Studies on critically ill patients receiving large intravenous doses and Mendelian randomization trials do not link sugar alcohols to significant cardiovascular risks. Sugar alcohols are also endogenously produced in the body, and while their increased production under certain conditions is not fully understood, it requires further research. This review discusses the physiology and metabolism of erythritol and xylitol, and other sugar alcohols, their roles in metabolomic profiling, effects on platelet aggregation and cardiovascular risk, related genetic disorders, vascular impacts, and usage in critically ill patients