Search Results (698)

Catheter ablation is the cornerstone of rhythm control in atrial fibrillation (AF), yet recurrence remains common, and obesity is among the most consistently implicated modifiable risk factors. Weight reduction and metabolic pharmacotherapy are increasingly used in the periprocedural period, but whether they act through a shared pathway has not been systematically examined. This narrative review compares the two approaches and asks whether metabolic agents confer protection beyond weight loss itself. Three observations argue that they do not act identically. First, the benefit of weight reduction is dose-dependent yet contingent on delivery: a structured, physician-led risk-factor program reduced 12-month arrhythmia recurrence (risk ratio 0.53), whereas nurse-led care that improved guideline adherence without structured delivery did not alter the primary endpoint. Second, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been associated with reduced recurrence across BMI strata despite producing only modest weight loss; notably, a randomized trial in patients without cardiovascular or metabolic comorbidity showed no additional benefit, whereas benefit was observed in patients with type 2 diabetes and heart failure. Third, glucagon-like peptide-1 receptor agonists (GLP-1RA) achieve greater weight loss but yield inconsistent recurrence data, and Mendelian randomization suggests their cardiometabolic benefit is largely BMI-mediated, whereas that of SGLT2i is weight-independent. Together, these observations are consistent with a working hypothesis of two partly distinct atrial substrates—an obesity-related substrate responsive to weight reduction, and a metabolic-inflammatory substrate that may respond to SGLT2i predominantly when metabolic comorbidity is present. This framework is hypothesis-generating: it rests on indirect, cross-study comparisons and has not been tested by formal mediation analysis. If confirmed, it would imply that the two interventions are complementary rather than interchangeable. Full article

Donkeys and horses diverged approximately 4 million years ago and exhibit substantial genetic, chromosomal, and physiologic differences. Although mostly studied in horses, metabolic syndrome represents a broader metabolic dysfunction with systemic consequences, such as obesity and laminitis, that can impact the quality of life of equids. This review summarizes the current knowledge of glucose and insulin regulation in healthy horses and donkeys and examines the pathophysiology of equine metabolic syndrome (EMS) in comparison with donkey metabolic syndrome (DMS), including insulin dysregulation, impaired glucose transport, adipose tissue dysfunction, and emerging evidence of systemic meta-inflammation and oxidative stress. Compared with horses, donkeys demonstrate distinct patterns of adipose deposition, different metabolic profiles, and altered glucose and insulin dynamics following oral soluble carbohydrate intake. While our understanding of donkey medicine has expanded in recent years, gaps in knowledge remain regarding mechanistic insights into glucose metabolism and dysregulation in donkeys. Finally, we evaluate current and emerging therapeutic strategies, including dietary management, exercise, nutraceuticals, and pharmacologic interventions such as metformin and sodium–glucose cotransporter 2 inhibitors (SGLT2is). While these therapeutic approaches have demonstrated efficacy in horses, evidence in donkeys remains extremely limited. This highlights a critical need for species-specific research to elucidate the pathophysiological mechanisms and optimize therapeutic strategies for donkeys. Full article

Diuretics remain indispensable for the treatment of congestion in cardiovascular disease, particularly in acute and chronic heart failure. Their principal clinical value is rapid symptom relief, reduction in filling pressures and facilitation of decongestion; however, a mortality benefit has not been consistently demonstrated. This distinction is clinically important because long-term diuretic exposure in patients without objective congestion may promote hypotension, renal dysfunction, electrolyte instability, neurohormonal activation, falls, cognitive impairment and avoidable polypharmacy. The challenge is therefore not whether diuretics should be used, but how intensively, for how long and under which monitoring strategy. In this narrative review, we summarize the pharmacology of major diuretic classes, the mechanisms of diuretic resistance, and the clinical consequences of potassium, sodium and magnesium disorders. We also discuss drug interactions, frailty, chronic kidney disease, pregnancy, heart failure with preserved ejection fraction and the emerging role of sodium–glucose cotransporter 2 inhibitors and adjunctive proximal-tubule strategies. A practical approach is proposed: use loop diuretics promptly when congestion is present, reassess response with symptoms, weight, urine output, renal function, electrolytes and congestion markers, and reduce or discontinue therapy once euvolemia is achieved and maintained. Deprescribing should be individualized, gradual and reversible, with explicit thresholds for restarting treatment. Optimized diuretic care requires the same discipline applied to disease-modifying heart failure therapy: phenotype recognition, dose minimization, close follow-up and avoidance of treatment inertia. Full article

Background/Objectives: Native valvular heart disease (VHD) lacks established lesion-modifying pharmacotherapy. Sodium–glucose cotransporter 2 inhibitors (SGLT2is) improve heart-failure and cardiorenal outcomes, but their relevance to VHD differs by phenotype and treatment setting. Methods: MEDLINE/PubMed, Scopus, Web of Science Core Collection and Cochrane CENTRAL were searched from inception to 27 July 2026, together with trial registries, conference proceedings and reference lists. Evidence was synthesized by clinical setting, study design and mechanistic proximity to valve tissue. Results: Functional/secondary mitral regurgitation (MR) currently provides the most convincing valve-related signal: EFFORT and DEFORM showed concordant reductions in MR severity with favorable remodeling surrogates, consistent with HF-directed unloading rather than a primary leaflet effect. DapaTAVI provides the strongest hard-outcome evidence after the mechanical correction of aortic stenosis, reducing the 1-year death/worsening-HF composite in selected high-risk patients. In 28,940 HF patients from the SHEBAHEART registry, SGLT2i use was associated with reduced death/HF hospitalization and a 28% lower adjusted risk of tricuspid-regurgitation progression, but these data remain observational. Native aortic-stenosis progression is supported only by target-trial emulation, and no dedicated clinical evidence exists for native aortic regurgitation. Conclusions: SGLT2is should be integrated into guideline-directed HF therapy when indicated. In secondary MR, reassessment after optimized therapy should precede mitral intervention when clinically appropriate. A post-TAVI benefit should be interpreted as cardiorenal/HF protection, not valve modification. The current evidence does not justify SGLT2is solely to modify an untreated native valve lesion. Full article

It is well-known that the morbidity and clinical burden of type 2 diabetes mellitus (T2DM) are predominantly associated with its chronic complications, in which fibrosis is a significant contributor. Recently, sodium–glucose cotransporter 2 (SGLT2) inhibitors have made a pivotal advancement in the therapeutic landscape not only improving glycemic control, but also demonstrating high effectiveness in the prevention and treatment of T2DM complications. In this work, we aimed to assess the transcription factors (TFs) mediating the effects of SGLT2 inhibitor empagliflozin (EMPA) treatment by a comprehensive analysis of the allele-specific expression (ASE) events utilizing the RNA-seq data. Initial logistic regression analysis of the in vitro transcriptomic data for EMPA-treated peripheral blood mononuclear cells (PBMCs) of three healthy donors revealed a significant inter-individual variation in ASE for 240 genes linked to EMPA treatment beyond the glucose-lowering effects. Then, 146 TFs were predicted to regulate the expression of the corresponding targets using motifbreakR and DESeq2. Among these, multiple TFs (including ATF3, ATF4, E2F1, EGR1, FOS, JUN, JUNB, IRF8, KLF6, KLF11, SNAI1, TWIST1, and ZEB1) were involved in the TGF-β/SMAD3 canonical profibrotic signaling cascade, pertinent to diabetes-related fibrosis, playing a significant role in the development of diabetic complications. Further analysis of the in vivo data for the PBMCs from ten T2DM patients initiating EMPA therapy identified 98 TFs related to the ASE variation in both in vitro and in vivo cohorts. To conclude, our integrative allele-specific approach enables the prediction of novel EMPA-responsive regulatory interactions and suggests the important mediators of the mechanisms underlying the effects of EMPA on human PBMCs. Full article

Background: Sodium–glucose co-transporter-2 (SGLT-2) inhibitors are widely prescribed for type 2 diabetes mellitus (T2DM) because of their cardiovascular and renoprotective benefits. However, their use is associated with euglycemic diabetic ketoacidosis (EDKA), a rare but potentially life-threatening complication characterized by severe ketoacidosis despite relatively normal blood glucose levels. Failure to discontinue SGLT-2 inhibitors before surgery, as recommended in current guidelines, together with perioperative fasting and surgical stress, increases the risk of EDKA. Diagnostic complexity is compounded when concurrent postoperative surgical complications provide an alternative explanation for persistent metabolic acidosis. Methods: A 71-year-old man with T2DM receiving uninterrupted empagliflozin underwent direct lateral interbody fusion under general anesthesia. On postoperative day 2, he developed severe high anion-gap metabolic acidosis (pH 7.204, HCO₃⁻ 10.1 mEq/L) with near-normal blood glucose levels (178 mg/dL). Pneumoperitoneum identified on imaging was attributed to Hemovac drain-related peritoneal injury, and emergent laparoscopic exploration was performed under a working diagnosis of surgical sepsis. Although surgical source control was successfully achieved, severe metabolic acidosis persisted postoperatively (pH 7.275). Euglycemic diabetic ketoacidosis is an uncommon diabetic complication associated with several perioperative risk factors, including prolonged fasting and surgical stress. Subsequent serum ketone analysis demonstrated markedly elevated beta-hydroxybutyrate levels (4.8 mmol/L), confirming co-existing EDKA. Results: Following empagliflozin discontinuation, targeted treatment with concurrent insulin–dextrose infusion resulted in complete resolution of acid-base imbalance within five days. Conclusions: A concurrent surgical complication appeared to mask EDKA and contributed to a delay in its recognition. In patients receiving SGLT-2 inhibitors, metabolic acidosis that persists after an apparent surgical cause has been addressed should prompt measurement of serum ketones, irrespective of the blood glucose concentration. Structured perioperative protocols for SGLT-2 inhibitor management and postoperative ketone surveillance may help to prevent similar events. Full article

Background and Objectives: Sodium–glucose cotransporter-2 (SGLT2) inhibitors provide cardio-renal protection in type 2 diabetes, but tolerability-related discontinuation is common, creating a need for effective replacement therapy. Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used as follow-on agents, yet the clinical course after such a switch has not been systematically characterized, and whether individual DPP-4 inhibitors differ in efficacy in this setting is unknown. Materials and Methods: We conducted a single-center retrospective cohort study at Chungnam National University Hospital (Daejeon, Republic of Korea) between January 2013 and January 2025, including 117 adults with type 2 diabetes who switched from an SGLT2 inhibitor to a DPP-4 inhibitor and met pre-specified criteria for medication stability and follow-up. The primary outcome was the change in glycated hemoglobin (HbA1c) from baseline to 3 months; secondary outcomes were changes in body weight, body mass index, blood pressure, and renal parameters. A pre-specified subgroup analysis compared teneligliptin (n = 60) with other DPP-4 inhibitors as a class (n = 57). Results: In the overall cohort, body weight rose by 0.7 kg and systolic blood pressure by 4.3 mmHg at 3 months (both p < 0.05), whereas HbA1c was unchanged (p = 0.157). In the subgroup analysis, HbA1c fell significantly with teneligliptin (−0.36%; 95% confidence interval, −0.62 to −0.10; p = 0.009) but not with other DPP-4 inhibitors (+0.13%). The between-group difference was −0.49% (95% confidence interval, −0.83 to −0.15; p = 0.005) and persisted after adjustment for baseline HbA1c and estimated glomerular filtration rate (p = 0.007). Conclusions: Switching preserved overall glycemic control at 3 months but produced modest, anticipated increases in body weight and blood pressure. Teneligliptin was associated with a greater HbA1c reduction than the pooled group of other DPP-4 inhibitors; this association persisted after adjustment for the two available baseline covariates but could not be adjusted for diabetes duration, medication adherence, diabetic complications, or other unmeasured factors. Because confounding by indication and other residual confounding cannot be excluded in this short-term, single-center analysis, this finding is hypothesis-generating only and requires confirmation in adequately powered prospective head-to-head trials. Importantly, this study evaluated only the glucose-lowering effect of the switch; because the cardio-renal protection of SGLT2 inhibition is not reproduced by DPP-4 inhibitors, a DPP-4 inhibitor should be regarded as an unavoidable substitute when an SGLT2 inhibitor cannot be maintained rather than a therapeutically equivalent replacement, and preserved HbA1c at 3 months does not establish clinical equivalence between the two strategies. Full article

Diabetic kidney disease (DKD) remains a major cause of advanced chronic kidney disease (CKD) and cardiovascular (CV) mortality, despite optimization of renin–angiotensin–aldosterone system (RAAS) blockade and the use of sodium–glucose cotransporter-2 inhibitors (SGLT2i). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are cardiometabolic agents with significant efficacy on glycemic control, body weight, blood pressure (BP), lipid profile, and systemic inflammation. In experimental studies, GLP-1 RAs showed direct renal effects by modulating natriuresis, intrarenal hemodynamics, oxidative stress, endothelial dysfunction, and tubular apoptosis. Randomized clinical trials and real-life analyses have demonstrated reductions in albuminuria and slowing of glomerular filtration rate (GFR) decline. The first study with a primary renal endpoint for semaglutide confirms its nephroprotective potential. This narrative review synthesizes the renal mechanisms involved. The clinical evidence for GLP-1 RA in DKD positions this class alongside SGLT2i and non-steroidal mineralocorticoid receptor antagonists (ns-MRAs) for the management of patients with type 2 diabetes mellitus (T2D), CKD, and very high cardiorenal risk. Full article

Cardiac senescence is not an isolated organ decline but a systemic consequence driven by pathological crosstalk between the heart and its peripheral metabolic organs. In this review, we discard the traditional organ–centric perspective and construct an integrated framework around multi-organ crosstalk axes, including the epicardial adipose tissue–heart axis, the skeletal muscle–heart axis, the gut–heart axis, and the kidney–heart axis. For each axis, we dissect the local molecular mediators—inflammatory cytokines, lipotoxic metabolites, microbiota-derived compounds such as trimethylamine N-oxide (TMAO), renin-angiotensin-aldosterone system (RAAS) effectors, and extracellular vesicle (EV) cargoes—and illustrate how they converge onto common pathways of oxidative stress, impaired autophagy, and cellular senescence. Importantly, we emphasize that these signals do not operate in isolation; they act synergistically through the circulation, converting local organ dysfunction into systemic cardiac aging via convergence onto shared senescence pathways. By redefining aging as a potentially modifiable multi-organ crosstalk, we propose emerging nodal points—senolytics, myokine mimetics, gut microbiota modulation, RAAS/sodium–glucose cotransporter 2 (SGLT2) inhibitors, and integrated lifestyle strategies—to block pathological crosstalk and delay cardiovascular aging. This framework shifts the research focus from isolated organs to systemic multi-organ crosstalk, providing new insights into cardiometabolic aging. Full article

Background: Hyperuricemia has long been linked to the progression of chronic kidney disease (CKD), although the role of serum uric acid (sUA) reduction in kidney preservation remains uncertain. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower sUA levels and exert renoprotective effects, but it is unclear whether these findings are mechanistically related. Methods: Adult patients with type 2 diabetes mellitus and hyperuricemia were included from a retrospective cohort. Patients treated with empagliflozin (n = 70) or dapagliflozin (n = 78) were pooled into a single group and compared with an allopurinol-treated group (n = 66). Exploratory mediation-informed analysis models assessed associations between treatment, changes in sUA (ΔsUA), and changes in estimated glomerular filtration rate (ΔeGFR) at 12 and 36 months. Dose–response and nonlinear associations between ΔsUA and ΔeGFR were additionally examined. Results: At 12 months, SGLT2 inhibitor treatment was associated with greater ΔsUA compared with allopurinol (B = 22.62, p = 0.040); its direct association with ΔeGFR remained significant after adjustment for ΔsUA (B = −6.14, p < 0.001). At 36 months, the association of treatment with ΔsUA was no longer significant, whereas association with ΔeGFR persisted (B = −11.8, p < 0.001). No dose–response or nonlinear relationship was identified between ΔsUA and ΔeGFR, while treatment remained an independent predictor of ΔeGFR at both time points. Conclusions: Reductions in sUA do not appear to mediate the renoprotective effects of SGLT2 inhibitors. The preservation of kidney function associated with SGLT2 inhibitor therapy is likely driven by mechanisms independent of sUA lowering. Full article

Background/Objectives: optimization of the therapeutic efficacy of antidiabetic agents is still a great challenge in the management of type 2 diabetes mellitus (T2DM), and attention is becoming more and more focused on the use of adjunctive agents that help target the drug action beyond the classic glycemic target. This study examined the effect of co-administration of an Artemisia herba-alba Asso (Asteraceae) aqueous extract on the glucose-lowering effect of dapagliflozin, a sodium–glucose cotransporter-2 (SGLT2) inhibitor. Methods: qualitative phytochemical screening and total phenolic and total flavonoid content were used to characterize the aqueous preparation. Male Wistar albino rats were divided into eight groups (10 rats each): four healthy and four diabetic rats induced with streptozotocin (STZ). Vehicle control, oral administration of an aqueous A. herba-alba preparation (0.39 g/kg twice daily), dapagliflozin (0.143 mg/kg/day), or a combination of both was given for 30 days. At baseline and days 7, 14, 21, and 30, glycated hemoglobin (HbA1c) was measured by nephelometry. Parallel fasting blood glucose (FBG) was monitored. Results: the diabetic animals treated with the combination regimen showed the greatest and most sustained decrease in HbA1c (from 4.42 ± 0.40% at baseline to 3.44 ± 0.17% at day 30; p < 0.001) and the greatest decrease in FBG (from 186.0 to 122.2 mg/dL). A. herba-alba monotherapy had little effect on HbA1c and had minimal effect on FBG (214.9 to 217.6 mg/dL); dapagliflozin monotherapy had a modest effect on HbA1c. The untreated diabetic controls (n = 10) showed a progressive increase in HbA1c from 4.45 ± 0.60% at 72 h post-induction to 11.90 ± 0.99% by day 30 (p < 0.001), consistent with delayed hemoglobin glycation relative to the rise in blood glucose. The repeated-measures ANOVA showed a highly significant interaction between time and treatment (p < 0.001). Conclusions: this study showed that the phytochemically defined aqueous A. herba-alba preparation is a beneficial adjunct to SGLT2 inhibitor therapy, an effect not observed with either treatment alone. Full article

Heart failure (HF) remains a major global health burden despite substantial therapeutic advances. Vericiguat, an oral soluble guanylate cyclase (sGC) stimulator, represents a distinct pharmacological strategy targeting impaired nitric oxide–sGC–cyclic guanosine monophosphate (NO–sGC–cGMP) signaling, a pathway closely linked to endothelial dysfunction, vascular stiffness, myocardial fibrosis, and adverse remodeling. This narrative review synthesizes the current evidence on the efficacy, safety, and clinical positioning of vericiguat across the heart failure spectrum, with a particular focus on worsening heart failure with reduced ejection fraction (HFrEF), while integrating recent trial data, updated guideline recommendations, and emerging real-world evidence to define its contemporary role in clinical practice. Randomized trials, subgroup analyses, and contemporary meta-analyses indicate that vericiguat provides a modest but clinically relevant reduction in HF-related outcomes, especially in high-risk patients with recent decompensation. However, its overall effect appears smaller than that of foundational therapies such as angiotensin receptor–neprilysin inhibitors and sodium–glucose cotransporter 2 inhibitors. Recently published data from the VICTOR program further refine the role of vericiguat in compensated outpatients with chronic HFrEF, showing a neutral primary outcome but providing supportive hypothesis-generating signals across a broader risk continuum while confirming a favorable safety profile. Overall, vericiguat should be regarded not as a replacement for cornerstone therapy but as a mechanistically complementary, risk-targeted adjunct for selected patients with persistent residual risk despite guideline-directed medical therapy. Full article

Sodium–glucose co-transporter 2 (SGLT2) inhibitors confer cardioprotection in patients with and without diabetes; however, whether SGLT2 is expressed in cardiac tissue and how these drugs act locally in the heart remains unclear. We investigated SGLT2 expression and the effects of empagliflozin in human iPSC-derived cardiac cells exposed to diabetogenic conditions. SGLT2 expression and the effects of empagliflozin were assessed in iPSC-derived cardiomyocytes, endothelial cells, and cardiac fibroblasts under acute diabetogenic conditions using protein expression and metabolic activity assays, and in a multicellular 3D cardiac microtissue model using metabolic activity and contraction analyses. SGLT2 was detected in all three iPSC-derived cardiac cell types with nuclear and perinuclear localisation; no membrane-bound expression was observed. Endothelial cell SGLT2 expression was elevated under diabetogenic conditions. Diabetogenic stress reduced metabolic activity in both cardiomyocytes and endothelial cells; empagliflozin partially rescued endothelial cell metabolic activity but had no effect in cardiomyocytes. Empagliflozin reversed diabetogenic stress-induced cardiac fibroblast activation. 3D cardiac microtissues under diabetogenic conditions exhibited prolonged relaxation time, reduced beat rate variability, and reduced metabolic activity. Empagliflozin maintained metabolic activity at levels comparable to those of the control but did not rescue relaxation time or beat rate variability. The responsiveness of non-myocytes (endothelial cells and cardiac fibroblasts) to empagliflozin, in the absence of any effect on cardiomyocytes, suggests that non-myocyte-mediated mechanisms may contribute to the clinically observed cardioprotection of SGLT2 inhibitors. Full article

Obesity and type 2 diabetes mellitus (T2DM) represent pandemic metabolic illnesses hallmarked by defective pancreatic β-cell function and blunted insulin release. As a conserved small GTPase (guanosine triphosphatase), ADP-ribosylation factor 6 (ARF6) governs fundamental cellular events encompassing vesicle trafficking, cytoskeleton remodeling and lipid metabolic turnover. Emerging data confirm that ARF6 acts as a master rheostat of glucose-stimulated insulin secretion (GSIS) in β-cells through downstream cell division control protein 42/Ras-related C3 botulinum toxin substrate 1 (Cdc42/Rac1) cascades. Pathogenic ARF6 hyperactivation triggers a cascade of β-cell lesions: mitochondrial impairment, autophagic suppression and exacerbated inflammatory signaling, accelerating the progression of obesity and T2DM. First-line therapeutics ranging from GLP-1 (Glucagon-like peptide-1) receptor agonists and metformin to SGLT2 (Sodium-Glucose Cotransporter 2) inhibitors partially restore metabolic homeostasis by rectifying aberrant ARF6-dependent signaling axes. This review comprehensively delineates ARF6’s canonical cellular roles, mechanistic bridges connecting ARF6 to β-cell failure and metabolic deterioration, and functional crosstalk between ARF6 and established anti-metabolic pharmacotherapies. We further address unresolved research gaps and prospective translational avenues, offering actionable perspectives to advance ARF6 as a tractable therapeutic target for obesity and T2DM management. Full article

Peritoneal ultrafiltration failure is a major complication of peritoneal dialysis and a common cause of technique failure often leading to hemodialysis. Chronic exposure to glucose-based dialysate contributes to inflammation, fibrosis, and peritoneal membrane dysfunction. This study evaluated the effects of dapagliflozin on peritoneal membrane function in patients with ultrafiltration failure undergoing continuous ambulatory peritoneal dialysis. In our pre–post observational study, 32 patients with high/high–average peritoneal transport status and ultrafiltration failure received dapagliflozin 10 mg daily for six months. Peritoneal equilibration tests using a 4.25% dextrose solution were performed during early peritoneal dialysis, at ultrafiltration failure, and after treatment. Ultrafiltration volume, dialysate-to-plasma creatinine ratio, dialysate glucose ratio, sodium dip, and clinical/biochemical parameters were assessed. Dapagliflozin treatment was found to be associated with higher ultrafiltration volume (480 mL vs. 90 mL at ultrafiltration failure, p < 0.001), preservation of the intraperitoneal glucose gradient, changes in the dialysate-to-plasma creatinine ratio, and altered sodium dip parameters. Favorable changes were also observed in blood pressure, body mass index, inflammatory markers, hemoglobin, albumin, sodium, bicarbonate, and glycemic indices. No serious adverse events were reported. These findings suggest that dapagliflozin may improve ultrafiltration efficiency and peritoneal membrane function in peritoneal dialysis patients with ultrafiltration failure. Further randomized controlled trials are warranted. Full article