With rising incidence, mortality and limited therapeutic options, heart failure with preserved ejection fraction (HFpEF) remains one of the most important topics in cardiovascular medicine today. Characterised by left ventricular diastolic dysfunction partially due to impaired Ca2+ homeostasis, one ion channel in particular, SarcoEndoplasmic Reticulum Ca2+-ATPase (SERCA2a), may play a significant role in its pathophysiology. A better understanding of the complex mechanisms interplaying to contribute to SERCA2a dysfunction will help develop treatments targeting it and thus address the growing clinical challenge HFpEF poses. This review examines the conflicting evidence present for changes in SERCA2a expression and activity in HFpEF, explores potential underlying mechanisms, and finally evaluates the drug and gene therapy trials targeting SERCA2a in heart failure. Recent positive results from trials involving widely used anti-diabetic agents such as sodium-glucose co-transporter protein 2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1) agonists offer advancement in HFpEF management. The potential interplay between these agents and SERCA2a regulation presents a novel angle that could open new avenues for modulating diastolic function; however, the mechanistic research in this emerging field is limited. Overall, the direct role of SERCA2a dysfunction in HFpEF remains undetermined, highlighting the need for well-designed pre-clinical studies and robust clinical trials.

Diabetic kidney disease (DKD) is a prevalent complication of diabetes mellitus (DM), and its incidence is increasing alongside the number of diabetes cases. Effective treatment and long-term management of DKD present significant challenges; thus, a deeper understanding of its pathogenesis is essential to address this issue. Chronic inflammation and abnormal cell death in the kidney closely associate with DKD development. Recently, there has been considerable attention focused on immune cell infiltration into renal tissues and its inflammatory response's role in disease progression. Concurrently, ferroptosis-a novel form of cell death-has emerged as a critical factor in DKD pathogenesis, leading to increased glomerular filtration permeability, proteinuria, tubular injury, interstitial fibrosis, and other pathological processes. The cardiorenal benefits of SGLT2 inhibitors (SGLT2-i) in DKD patients have been demonstrated through numerous large clinical trials. Moreover, further exploratory experiments indicate these drugs may ameliorate serum and urinary markers of inflammation, such as TNF-α, and inhibit ferroptosis in DKD models. Consequently, investigating the interplay between ferroptosis and innate immune and inflammatory responses in DKD is essential for guiding future drug development. This review presents an overview of ferroptosis within the context of DKD, beginning with its core mechanisms and delving into its potential roles in DKD progression. We will also analyze how aberrant innate immune cells, molecules, and signaling pathways contribute to disease progression. Finally, we discuss the interactions between ferroptosis and immune responses, as well as targeted therapeutic agents, based on current evidence. By analyzing the interplay between ferroptosis and innate immunity alongside its inflammatory responses in DKD, we aim to provide insights for clinical management and drug development in this area.

Inflammation may play an important pathophysiological role in the development and progression of heart failure (HF). Interleukin (IL)-6 is a circulating cytokine and is the main regulator of the release of C-reactive protein (CRP).

The authors examined the association between IL-6 and high-sensitivity (hs)-CRP and outcomes in patients with HFrEF in the DAPA-HF trial and their relationship with the effect of dapagliflozin.

Inclusion criteria included: 1) NYHA functional class II-IV; 2) left ventricular ejection fraction ≤40%; 3) elevated N-terminal pro-B-type natriuretic peptide; and 4) estimated glomerular filtration rate ≥30 mL/min/1.73 m2. The primary outcome was a composite of a worsening HF event or cardiovascular death. IL-6 and hs-CRP were measured at baseline and 12 months (Roche Diagnostics). The associations between IL-6 and hs-CRP and outcomes were adjusted for known prognostic variables, including NT-proBNP.

Among 2,940 patients, median IL-6 and hs-CRP at baseline were 6.01 pg/mL (Q1-Q3: 4.18-9.28 pg/mL) and 2.05 mg/L (Q1-Q3: 0.83-4.9 mg/L), respectively. Baseline IL-6 tertiles (T) were: T1 ≤4.72 pg/mL; T2 4.73-7.89 pg/mL; and T3 ≥7.90 pg/mL. The adjusted risks of the primary outcome relative to T1 were as follows: T2 = HR 1.34 (95% CI: 1.04-1.73) and T3 = HR 1.80 (95% CI: 1.41-2.31). A rise in IL-6 between baseline and 12 months was associated with worse outcomes. The beneficial effect of dapagliflozin on the primary outcome was consistent regardless of IL-6 concentration (continuous interaction P = 0.57), with similar results for hs-CRP. Dapagliflozin did not reduce IL-6 or hs-CRP at 12 months.

In DAPA-HF, elevated IL-6 and hs-CRP levels were each associated with the risk of worsening HF or cardiovascular death. Dapagliflozin reduced the risk of adverse outcomes regardless of baseline IL-6 or hs-CRP. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).

The kidneys produce daily about 180 liters of urine but only about 2 liters are excreted. The proximal tubule plays an important role in reabsorbing the majority of filtered urine and many metabolites such as sugars, amino acids, salts or phosphate that are contained in this large volume. Reabsorption of these important metabolites is mediated by a diverse group of highly specialized transport proteins. Another group of transport proteins in the proximal tubule is responsible for the active secretion of metabolic waste products or toxins and drugs into urine. All these transporters have in common that they are directly linked to kidney metabolism and indirectly to whole-body metabolism and functions. In recent years, it has become evident that modulation of these transporters may influence the onset, progression and consequences of kidney disease. This review summarizes recent developments in this field and discusses some examples of drugs already in clinical use or in development. The examples include inhibitors of sugar transporters (SGLT2 inhibitors) that are successfully used in patients with kidney disease, diabetes or heart failure. Likewise, indirect inhibitors (acetazolamide) of an transporter absorbing sodium in exchange for protons (NHE3) are used mostly in patients with heart failure or for prevention of high altitude disease, while direct inhibitors show promise in preclinical studies to reduce damage in episodes of acute kidney disease or high blood pressure. Modulators of transporters mediating the excretion of urate have been used in patients with gout and are also discussed to prevent kidney disease. Novel drugs in development target transporters for phosphate, amino acids, or toxin and drug excretion and may be helpful for specific conditions associated with kidney disease. The advantages and challenges associated with these (novel) drugs targeting proximal tubule transport are discussed.

The proximal tubule is responsible for reabsorbing about 60% of filtered solutes and water and is critical for the secretion of metabolic waste products, drugs and toxins. A large number of highly specialized ion channels and transport proteins belonging to the SLC and ABC transporter families are involved. Their activity is directly or indirectly linked to ATP consumption and requires large quantities of energy and oxygen supply. Moreover, the activity of these transporters is often coupled to the movement of Na+ ions thus influencing also salt and water balance, as well as transport and regulatory processes in downstream segments. Because of their relevance for systemic ion balance, for renal metabolism or for affecting regulatory processes, proximal tubule transporters are attractive targets for existing drug and for novel strategies to reduce kidney disease progression or to alleviate the consequences of decreased kidney function. In this review, the relevance of some major proximal tubule transport systems as drug targets in individuals with chronic kidney disease (CKD) is discussed. Inhibitors of the sodium-glucose cotransporter 2, SGLT2, are now part of standard therapy in patients with CKD and/or heart failure. Also, indirect inhibition of Na+/H+-exchangers by carbonic anhydrase inhibitors and uricosuric drugs have been used for decades. Inhibition of phosphate and amino acid transporters have recently been proposed as novel principles to remove excess phosphate or to protect the proximal tubule metabolically, respectively. In addition, organic cation and anion transporters involved in drug and toxin excretion may serve as targets of new drugs. The advantages and challenges associated with (novel) drugs targeting proximal tubule transport are discussed.

Inflammation plays a major role in the etiology of chronic heart failure and in inducing the progression to end-stage heart failure. This chronic inflammation, which accompanies heart failure, is not only local but also systemic and is usually in a state of low-grade but constant activation. Because there is an interrelation between systemic inflammation and neurohormonal activation, almost all anti-remodeling classes of medication have been evaluated for a potential and hidden anti-inflammatory effect. This study aimed to evaluate the effect of sodium-glucose co-trans-porter 2 inhibitors (SGLT2i) (Dapagliflozin or Empagliflozin) on inflammation measured by C-reactive protein levels, erythrocyte sedimentation rate (ESR) and fibrinogen in patients with chronic heart failure when administered together with other standard heart failure medications. We retrospectively enrolled 220 patients with chronic heart failure admitted to our hospital from January 2021 until March 2023. The study included two visits, T0 (the initial visit) and T1 (after six months), to assess if SGLT2i initiation after the first visit (T0) had an effect on the levels of inflammatory biomarkers. SGLT2i showed a reduction in fibrinogen levels, an effect that was present both in heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) phenotypes. This was opposite to the dynamics of inflammatory markers in patients who did not receive SGLT2i, where the fibrinogen levels increased in HFrEF and HFpEF subgroups. SGLT2i proved an anti-inflammatory effect, showing a statistically significant reduction in fibrinogen levels in chronic heart failure, irrespective of the phenotype.

Background and Objectives: Insulin resistance (IR) is a key factor involved in the development of type 2 diabetes (T2D). Besides its role in the pathogenesis of T2D, insulin resistance is associated with impairment of glycemic control, reduced achievement of glycemic targets, and increases in cardiovascular risk and diabetes complications, being thus a negative prognosis factor. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are therapies for T2D which demonstrated, besides glycemic control, improvements of biomarkers traditionally associated with IR and inflammation. This study aimed to evaluate the impact of SGLT2i treatment on IR and inflammation biomarkers in patients with T2D. Materials and Methods: In a retrospective study, 246 patients with T2D treated with SGLT2i for a median of 5 years were evaluated regarding IR (estimated glucose disposal rate-eGDR, triglyceride/glucose index, triglyceride/HDLc index) and inflammation biomarkers (neutrophils to lymphocyte ratio, platelets to lymphocytes ratio and C-reactive protein) before and after intervention with SGLT2i. Results: After a median 5 years of SGLT2i treatment, patients with T2D had a higher eGDR (6.07 vs. 5.24 mg/kg/min; p < 0.001), lower triglyceride/HDLc ratio (3.34 vs. 3.52, p < 0.001) and lower triglyceride/glucose index (9.23 vs. 9.58; p < 0.001). The inflammation biomarkers decreased after SGLT2i therapy: C-reactive protein (3.07 mg/L vs. 4.37 mg/L), NLR (0.68 vs. 0.72; p < 0.001), and PLR (115 vs. 122; p < 0.001). Intervention with SGLT2i also improved the biomarkers associated with diabetes complications and cardiovascular risk: HbA1c (7.1% vs. 8.4%; p < 0.001), body mass index (30.0 vs. 31.5 kg/m2; p < 0.001) and urinary albumin to creatinine ratio (4.75 vs. 11.00 mg/g; p < 0.001). Conclusions: Treatment with SGLT2i in patients with T2D leads to decreases in IR and inflammation. These mechanisms may partially explain the additional cardiovascular and renal risk reductions associated with SGLT2i therapy, alongside the improvements in glycemic control, in patients with T2D.

Diabetes mellitus (DM) is a multifaceted disorder with a pandemic spread and a remarkable burden of cardiovascular mortality and morbidity. Diabetic cardiomyopathy (DBCM) has been increasingly recognized as the development of cardiac dysfunction, which is accompanied by heart failure (HF) symptoms in the absence of obvious reasons like ischemic heart disease, hypertension, or valvulopathies. Several pathophysiological mechanisms have been proposed, including metabolic disorders (e.g., glycation products), oxidative stress, low-grade inflammation, mitochondrial dysfunction, etc., which should guide the development of new therapeutic strategies. Up to now, HF treatment has not differed between patients with and without diabetes, which limits the expected benefits despite the high cardiovascular risk in the former group. However, DBCM patients may require different management, which prioritize anti-diabetic medications or testing other novel therapies. This review aims to appraise the challenges and prospectives of the individualized pharmaceutical therapy for DBCM.

An 85-year-old man with recently diagnosed metastatic EGFR+ lung adenocarcinoma treated with osimertinib presented after 1 month of therapy in decompensated congestive heart failure along with atrial fibrillation, prolonged QTc and acute kidney injury. Osimertinib was held. His hemodynamic status was optimized, and he was started on cardioprotective medications (losartan and metoprolol succinate), and LVEF recovered. However, after reintroducing osimertinib, LVEF reduced, indicating possible osimertinib-induced cardiomyopathy. An SGLT2 inhibitor was added for cardioprotection before another rechallenge of osimertinib. SGLT2 inhibitors are a powerful tool for heart failure and may have a potential secondary benefit in ameliorating cardiotoxic processes. Although their use in osimertinib-induced cardiomyopathy has not been well-established, current heart failure guidelines and emerging research support its use in this setting. This case and the accompanying literature review highlight the novel use of SGLT2 inhibitors coupled with regular clinical and imaging monitoring, as a compelling intervention for osimertinib-induced cardiomyopathy.

Chronic kidney disease and end-stage kidney disease (ESKD) are well-established risk factors for cardiovascular disease (CVD), the leading cause of mortality in the dialysis population. Conventional therapies, such as statins, blood pressure control, and renin-angiotensin-aldosterone system blockade, have inadequately addressed this cardiovascular risk, highlighting the unmet need for effective treatment strategies. Sodium-glucose transporter 2 (SGLT2) inhibitors have demonstrated significant renal and cardiovascular benefits among patients with type 2 diabetes, heart failure, or CKD at risk of progression. Unfortunately, efficacy data in dialysis patients is lacking as ESKD was an exclusion criterion for all major clinical trials of SGLT2 inhibitors. This review explores the potential of SGLT2 inhibitors in improving cardiovascular outcomes among patients with ESKD, focusing on their direct cardiac effects.

Recent clinical and preclinical studies have shown promising data for the application of SGLT2 inhibitors to the dialysis population. SGLT2 inhibitors may provide cardiovascular benefits to dialysis patients, not only indirectly by preserving the remaining kidney function and improving anemia but also directly by lowering intracellular sodium and calcium levels, reducing inflammation, regulating autophagy, and alleviating oxidative stress and endoplasmic reticulum stress within cardiomyocytes and endothelial cells. This review examines the current clinical evidence and experimental data supporting the use of SGLT2 inhibitors, discusses its potential safety concerns, and outlines ongoing clinical trials in the dialysis population. Further research is needed to evaluate the safety and effectiveness of SGLT2 inhibitor use among patients with ESKD.

Heart failure (HF) is a major global health challenge, particularly among individuals with type 2 diabetes mellitus (T2DM), who are at significantly higher risk of developing HF. Diabetic cardiomyopathy, a unique form of heart disease, often progresses silently until advanced stages. Recent research has focused on sodium-dependent glucose transporter 2 inhibitors (SGLT2i), originally developed for hyperglycemia, which have shown potential in reducing cardiovascular risks, including HF hospitalizations, irrespective of diabetic status. In this editorial we comment on the article by Grubić Rotkvić et al published in the recent issue of the World Journal of Cardiology. The investigators examined the effects of SGLT2i on myocardial function in T2DM patients with asymptomatic HF, finding significant improvements in stroke volume index and reductions in systemic vascular resistance, suggesting enhanced cardiac output. Additionally, SGLT2i demonstrated anti-inflammatory and antioxidant effects, as well as blood pressure reduction, though the study's limitations-such as small sample size and observational design-necessitate larger randomized trials to confirm these findings. The study underscores the potential of early intervention with SGLT2i in preventing HF progression in T2DM patients.

The relationship of hypoglycemic drugs, inflammatory proteins and gallbladder diseases remain unknown.

Four hypoglycemic drugs were selected as exposure: glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), and metformin. The outcome were two gallbladder diseases: cholecystitis and cholelithiasis. Mendelian Randomization (MR) was employed to determine the association between hypoglycemic drugs and gallbladder diseases.

DPP-4i and SGLT-2i had no effect on cholecystitis and cholelithiasis. However, a causal relationship was found between inhibition of ETFDH gene, a target of metformin expressed in cultured fibroblasts, and cholelithiasis (OR: 0.84, 95 %CI: (0.72,0.97), p = 0.021), as well as between GLP1R expression in the brain caudate basal ganglia and cholecystitis (OR: 1.29, 95 %CI: (1.11,1.49), p = 0.001). The effect of ETFDH inhibition on cholelithiasis through Interleukin-10 receptor subunit beta (IL-10RB) levels and Neurotrophin-3 (NT-3) levels, with a mediated proportion of 8 % and 8 %, respectively.

Metformin plays a protective role in cholelithiasis, while GLP-1RA have a harmful effect on the risk of cholecystitis. Metformin may reduce the risk of cholelithiasis by modulating the levels of Neurotrophin-3 (NT-3) and Interleukin-10 receptor subunit beta (IL-10RB). Further clinical and mechanistic studies are required to confirm these findings.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as pivotal medications for heart failure, demonstrating remarkable cardiovascular benefits extending beyond their glucose-lowering effects. The unexpected cardiovascular advantages have intrigued and prompted the scientific community to delve into the mechanistic underpinnings of these novel actions. Preclinical studies have generated many mechanistic theories, ranging from their renal and extrarenal effects to potential direct actions on cardiac muscle cells, to elucidate the mechanisms linking these drugs to clinical cardiovascular outcomes. Despite the strengths and limitations of each theory, many await validation in human studies. Furthermore, whether SGLT2 inhibitors confer therapeutic benefits in specific subsets of cardiomyopathies akin to their efficacy in other heart failure populations remains unclear. By examining the shared pathological features between heart failure resulting from vascular diseases and other causes of cardiomyopathy, certain specific molecular actions of SGLT2 inhibitors (particularly those targeting cardiomyocytes) would support the concept that these medications will yield therapeutic benefits across a broad range of cardiomyopathies. This article aims to discuss the important mechanisms of SGLT2 inhibitors and their implications in hypertrophic and dilated cardiomyopathies. Furthermore, we offer insights into future research directions for SGLT2 inhibitor studies, which hold the potential to further elucidate the proposed biological mechanisms in greater detail.

To conduct post hoc analyses of the VERTIS CV (NCT01986881) trial to explore the effects of ertugliflozin on serum uric acid (UA) and gout-related outcomes.

Participants with type 2 diabetes and atherosclerotic cardiovascular disease were randomised (1:1:1) to placebo, ertugliflozin 5 mg or ertugliflozin 15 mg. Mean UA over time (260 weeks) was evaluated for pooled ertugliflozin versus placebo overall, and by baseline quintile of UA (≤4.3 mg/dL [≤255.8 µmol/L], >4.3-5.1 mg/dL [>255.8-303.4 µmol/L], >5.1-5.8 mg/dL [>303.4-345.0 µmol/L], >5.8-6.9 mg/dL [>345.0-410.4 µmol/L] and >6.9 mg/dL [>410.4 µmol/L]), glycated haemoglobin level, albuminuria status, estimated glomerular filtration rate and KDIGO (Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease) risk category. The effect of ertugliflozin on a composite of gout onset or initiation of anti-gout medication was assessed.

The mean UA levels at baseline were 5.67 and 5.62 mg/dL in the placebo and ertugliflozin groups, respectively. Ertugliflozin reduced UA over Weeks 6-260 compared with placebo, with least squares mean (LSM) changes (95% confidence interval [CI]) from baseline at Week 260 of 0.07 mg/dL (-0.02, 0.15) and -0.19 mg/dL (-0.25, -0.13) in the placebo and pooled ertugliflozin groups, respectively. At Week 260, placebo-adjusted LSM change (95% CI) from baseline in UA was -0.26 mg/dL (-0.36, -0.16) with ertugliflozin. Ertugliflozin was associated with reductions in UA across baseline UA quintiles compared with placebo. The incidence of the composite of gout-related outcomes was 84/2539 (3.3%) for placebo and 133/5091 (2.6%) for ertugliflozin (hazard ratio for the composite 0.76 [95% CI 0.580, 1.002]).

Ertugliflozin was generally associated with lowering UA overall and across subgroups compared with placebo, and numerically reduced rates of gout-related outcome events.

Diabetes mellitus and heart failure are two diseases that are commonly found together, in particular in older patients. High blood glucose has a detrimental effect on the cardiovascular system, and worse glycemic control contributes to the onset and the recrudesce of heart failure. Therefore, any specific treatment aimed to reduce glycated hemoglobin may, in turn, have a beneficial effect on heart failure. Sodium-glucose cotransporter-2 inhibitors have been initially developed for the treatment of type 2 diabetes mellitus, and their significant action is to increase glycosuria, which in turn causes a reduction in glucose blood level and contributes to the reduction of cardiovascular risk. However, recent clinical trials have progressively demonstrated that the glycosuric effect of the sodium-glucose cotransporter-2 inhibitors also have a diuretic effect, which is a crucial target in the management of patients with heart failure. Additional studies also documented that sodium-glucose cotransporter-2 inhibitors improve the therapeutical management of heart failure, independently by the glycemic control and, therefore, by the presence of diabetes mellitus. In this review, we analyzed studies and trials demonstrating the efficacy of sodium-glucose cotransporter-2 inhibitors in treating chronic and acute heart failure.

Heart failure (HF) is a debilitating clinical syndrome affecting 64.3 million patients worldwide. More than 50% of HF cases are attributed to HF with preserved ejection fraction (HFpEF), an entity growing in prevalence and mortality. Although recent breakthroughs reveal the prognostic benefits of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in HFpEF, there is still a lack of effective pharmacological therapy available. This highlights a major gap in medical knowledge that must be addressed. Current evidence attributes HFpEF pathogenesis to an interplay between cardiometabolic comorbidities, inflammation, and renin-angiotensin-aldosterone-system (RAAS) activation, leading to cardiac remodelling and diastolic dysfunction. However, conventional RAAS blockade has demonstrated limited benefits in HFpEF, which emphasises that alternative therapeutic targets should be explored. Presently, there is limited literature examining the use of anti-inflammatory HFpEF therapies despite growing evidence supporting its importance in disease progression. Hence, this review aims to explore current perspectives on HFpEF pathogenesis, including the importance of inflammation-driven cardiac remodelling and the therapeutic potential of anti-inflammatory therapies.

To estimate individual treatment effects (ITEs) of sodium-glucose co-transporter-2 inhibitors (SGLT2is) on lowering the risk of developing chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) and to identify those most probable to benefit from treatment.

This study followed a T2D cohort from Ramathibodi Hospital, Thailand, from 2015 to 2022. A counterfactual model was constructed to predict factual and counterfactual risks of CKD if patients did/did not receive SGLT2is. ITEs were estimated by subtracting the factual risk from the counterfactual risk of CKD.

There were 1619 and 15 879 patients included in the SGLT2i and non-SGLT2i groups, respectively. The estimated ITEs varied from -1.19% to -17.51% with a median of -4.49%, that is, 50% of patients had a 4.49% or greater lower CKD risk if they received an SGLT2i. Patients who gained the greatest benefit from SGLT2is were more probable to be male, aged at least 60 years, with a history of diabetes duration of at least 3 months, hypertension, peripheral arterial disease, diabetic retinopathy and low high-density lipoprotein cholesterol.

Our prediction model provides individualized information that helps target T2D patients who may benefit more from SGLT2is. This could help clinical decision making and implementation of personalized medicine in clinical practice, especially in resource-limited settings.

To compare the risks of gastric cancer and other gastric diseases in patients with type-2 diabetes mellitus (T2DM) exposed to sodium-glucose cotransporter 2 inhibitors (SGLT2I), dipeptidyl peptidase-4 inhibitors (DPP4I) or glucagon-like peptide-1 receptor agonists (GLP1a).

This was a population-based cohort study of prospectively collected data on patients with T2DM prescribed SGLT2I, DPP4I or GLP1a between January 1st 2015 and December 31st 2020 from Hong Kong. The outcomes were new-onset gastric cancer, peptic ulcer (PU), acute gastritis, non-acute gastritis, and gastroesophageal reflux disease (GERD). Propensity score matching (1:1) using the nearest neighbour search was performed, and multivariable Cox regression was applied. A three-arm comparison between SGLT2I, DPP4I and GLP1a was conducted using propensity scores with inverse probability of treatment weighting.

A total of 62,858 patients (median age: 62.2 years old [SD: 12.8]; 55.93% males; SGLT2I: n = 23,442; DPP4I: n = 39,416) were included. In the matched cohort, the incidence of gastric cancer was lower in SGLT2I (Incidence rate per 1000 person-year, IR: 0.32; 95% confidence interval, CI 0.23-0.43) than in DPP4I (IR per 1000 person-year: 1.22; CI 1.03-1.42) users. Multivariable Cox regression found that SGLT2I use was associated with lower risks of gastric cancer (HR 0.30; 95% CI 0.19-0.48), PU, acute gastritis, non-acute gastritis, and GERD (p < 0.05) compared to DPP4I use. In the three-arm analysis, GLP1a use was associated with higher risks of gastric cancer and GERD compared to SGLT2I use.

The use of SGLT2I was associated with lower risks of new-onset gastric cancer, PU, acute gastritis, non-acute gastritis, and GERD after matching and adjustments compared to DPP4I use. SGLT2I use was associated with lower risks of GERD and gastric cancer compared to GLP1a use.

A typical consequence of type 2 diabetes mellitus, diabetic kidney disease (DKD) is a significant risk factor for end-stage renal disease. The pathophysiology of diabetic kidney disease (DKD) is mainly associated with the immune system, which involves adhesion molecules and growth factors disruption, excessive expression of inflammatory mediators, decreased levels of anti-inflammatory mediators, and immune cell infiltration in the kidney. Dendritic cells are professional antigen-presenting cells acting as a bridge connecting innate and adaptive immune responses. The anti-inflammatory subset of DCs is also capable of modulating inflammation. Autologous anti-inflammatory dendritic cells can be made by in vitro differentiation of peripheral blood monocytes and utilized as a cell-based therapy. Treatment with anti-inflammatory cytokines, immunosuppressants, and substances derived from pathogens can induce tolerogenic or anti-inflammatory features in ex vivo-generated DCs. It has been established that targeting inflammation can alleviate the progression of DKD. Recent studies have focused on the potential of dendritic cell-based therapies to modulate immune responses favorably. By inducing a tolerogenic phenotype in dendritic cells, it is possible to decrease the inflammatory response and subsequent kidney damage. This article highlights the possibility of using anti-inflammatory DCs as a cell-based therapy for DKD through its role in controlling inflammation.

Diabetes is a chronic endocrine disorder that negatively affects various body systems, including the nervous system. Diabetes can cause or exacerbate various neurological disorders, and diabetes-induced neurodegeneration can involve several mechanisms such as mitochondrial dysfunction, activation of oxidative stress, neuronal inflammation, and cell death. In recent years, the management of diabetes-induced neurodegeneration has relied on several types of drugs, including sodium-glucose cotransporter-2 (SGLT2) inhibitors, also called gliflozins. In addition to exerting powerful effects in reducing blood glucose, gliflozins have strong anti-neuro-inflammatory characteristics that function by inhibiting oxidative stress and cell death in the nervous system in diabetic subjects. This review presents the molecular pathways involved in diabetes-induced neurodegeneration and evaluates the clinical and laboratory studies investigating the neuroprotective effects of gliflozins against diabetes-induced neurodegeneration, with discussion about the contributing roles of diverse molecular pathways, such as mitochondrial dysfunction, oxidative stress, neuro-inflammation, and cell death. Several databases-including Web of Science, Scopus, PubMed, Google Scholar, and various publishers, such as Springer, Wiley, and Elsevier-were searched for keywords regarding the neuroprotective effects of gliflozins against diabetes-triggered neurodegenerative events. Additionally, anti-neuro-inflammatory, anti-oxidative stress, and anti-cell death keywords were applied to evaluate potential neuronal protection mechanisms of gliflozins in diabetes subjects. The search period considered valid peer-reviewed studies published from January 2000 to July 2023. The current body of literature suggests that gliflozins can exert neuroprotective effects against diabetes-induced neurodegenerative events and neuronal dysfunction, and these effects are mediated via activation of mitochondrial function and prevention of cell death processes, oxidative stress, and inflammation in neurons affected by diabetes. Gliflozins can confer neuroprotective properties in diabetes-triggered neurodegeneration, and these effects are mediated by inhibiting oxidative stress, inflammation, and cell death.

SGLT-2i are increasingly recognized for their benefits in patients with cardiometabolic risk factors. Additionally, emerging evidence suggests potential applications in acute illnesses, including COVID-19. This systematic review aims to evaluate the effects of SGLT-2i in patients facing acute illness, particularly focusing on SARS-CoV-2 infection.

Following PRISMA guidelines, a systematic search of PubMed, Scopus, medRxiv, Research Square, and Google Scholar identified 22 studies meeting inclusion criteria, including randomized controlled trials and observational studies. Data extraction and quality assessment were conducted independently.

Out of the 22 studies included in the review, six reported reduced mortality in DM-2 patients taking SGLT-2i, while two found a decreased risk of hospitalization. Moreover, one study demonstrated a lower in-hospital mortality rate in DM-2 patients under combined therapy of metformin plus SGLT-2i. However, three studies showed a neutral effect on the risk of hospitalization. No increased risk of developing COVID-19 was associated with SGLT-2i use in DM-2 patients. Prior use of SGLT-2i was not associated with ICU admission and need for MV. The risk of acute kidney injury showed variability, with inconsistent evidence regarding diabetic ketoacidosis.

Our systematic review reveals mixed findings on the efficacy of SGLT-2i use in COVID-19 patients with cardiometabolic risk factors. While some studies suggest potential benefits in reducing mortality and hospitalizations, others report inconclusive results. Further research is needed to clarify optimal usage and mitigate associated risks, emphasizing caution in clinical interpretation.

Postoperative atrial fibrillation (POAF) is one of the most common types of acute AF and can complicate the treatment course of approximately one third of patients undergoing cardiac surgery. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are among the newest antidiabetic drugs which can be therapeutic options for preventing POAF by different mechanisms.

Empagliflozin to Prevent POAF (EMPOAF) is an interventional, investigator-initiated, double-blind, placebo-controlled, multicenter, randomized controlled trial which will be conducted in two referral teaching cardiology hospitals in Tehran. Four-hundred ninety-two adult patients who are scheduled for elective isolated coronary artery bypass graft (CABG) surgery will be randomly assigned to one of the groups of intervention (empagliflozin 10 mg daily) or placebo starting at least 3 days before surgery until discharge. Key exclusion criteria are a history of diabetes mellitus, AF, ketoacidosis, or recurrent urinary tract infections along with severe renal or hepatic impairment, unstable hemodynamics, and patients receiving SGLT2 inhibitors for another indication. The primary outcome will be the incidence of POAF. Key secondary endpoints will be the composite rate of life-threatening arrhythmias, postoperative acute kidney injury, hospitalization length, in-hospital mortality, stroke, and systemic embolization. Key safety endpoints will be the rate of life-threatening and/or genitourinary tract infections, hypoglycemia, and ketoacidosis.

EMPOAF will prospectively evaluate whether empagliflozin 10 mg daily can reduce the rate of POAF in patients undergoing elective CABG. Enrolment into this study has started by November 2023 and is expected to be ended before the end of 2025.

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) are a revolutionary treatment for type 2 diabetes (T2D) with cardiovascular, kidney, and serum urate-lowering benefits.

To compare risk of incident gout and rate of recurrent flares between patients with T2D initiating SGLT2i vs sulfonylurea, most common second-line glucose-lowering therapy, when added to metformin monotherapy.

This sequential, propensity score-matched, new-user comparative effectiveness study using target trial emulation framework included adults with T2D receiving metformin monotherapy in a Canadian general population database from January 1, 2014, to June 30, 2022.

Initiation of SGLT2i vs sulfonylurea.

The primary outcome was incident gout diagnosis, ascertained by emergency department (ED), hospital, outpatient, and medication dispensing records. Secondary outcomes were gout-primary hospitalizations and ED visits and major adverse cardiovascular events (MACE), as well as recurrent flare rates among prevalent gout patients. Heart failure (HF) hospitalization was assessed as positive control outcome and osteoarthritis encounters as negative control. For target trial emulations, we used Cox proportional hazards and Poisson regressions with 1:1 propensity score matching (primary analysis) and overlap weighting (sensitivity analysis). The analysis was conducted from September to December, 2023.

Among 34 604 propensity score matched adults with T2D initiating SGLT2i or sulfonylurea (20 816 [60%] male, mean [SD] age, 60 [12.4] years), incidence of gout was lower among SGLT2i initiators (4.27 events per 1000 person-years) than sulfonylurea initiators (6.91 events per 1000 person-years), with a hazard ratio (HR) of 0.62 (95% CI, 0.48-0.80) and a rate difference (RD) of -2.64 (95% CI, -3.99 to -1.29) per 1000 person-years. Associations persisted regardless of sex, age, or baseline diuretic use. SGLT2i use was also associated with fewer recurrent flares among gout patients (rate ratio, 0.67; 95% CI, 0.55-0.82; and RD, -20.9; 95% CI, -31.9 to -10.0 per 1000 person-years). HR and RD for MACE associated with SGLT2i use were 0.87 (95% CI, 0.77-0.98) and -3.58 (95% CI, -6.19 to -0.96) per 1000 person-years. For control outcomes, SGLT2i users had lower risk of HF (HR, 0.53; 95% CI, 0.38-0.76), as expected, with no difference in osteoarthritis (HR, 1.11; 95% CI, 0.94-1.34). Results were similar when applying propensity score overlap weighting.

In this population-based cohort study, the gout and cardiovascular benefits associated with SGLT2i in these target trial emulations may guide selection of glucose-lowering therapy in patients with T2D, at risk for or already with gout.

Plaque erosion (PE), a distinct etiology of acute coronary syndromes (ACSs), is often overshadowed by plaque ruptures (PRs). Concerning its epidemiology, PE has garnered increasing recognition, with recent studies revealing its prevalence to be approximately 40% among ACS patients, challenging earlier assumptions based on autopsy data. Notably, PE exhibits distinct epidemiological features, preferentially affecting younger demographics, particularly women, and often manifesting as a non-ST-segment elevation myocardial infarction. There are seasonal variations, with PE events being less common in winter, potentially linked to physiological changes and cholesterol solidification, while peaking in summer, warranting further investigation. Moving to molecular mechanisms, PE presents a unique profile characterized by a lesser degree of inflammation compared to PR, with endothelial shear stress emerging as a plausible molecular mechanism. Neutrophil activation, toll-like receptor-2 pathways, and hyaluronidase 2 expression are among the factors implicated in PE pathophysiology, underscoring its multifactorial nature. Advancements in intravascular imaging diagnostics, particularly optical coherence tomography and near-infrared spectroscopy coupled with intravascular ultrasound, offer unprecedented insights into plaque composition and morphology. Artificial intelligence algorithms show promise in enhancing diagnostic accuracy and streamlining image interpretation, augmenting clinician decision-making. Therapeutically, the management of PE evolves, with studies exploring less invasive approaches such as antithrombotic therapy without stenting, particularly in cases identified early through intravascular imaging. Additionally, the potential role of drug-coated balloons in reducing thrombus burden and minimizing future major adverse cardiovascular events warrants further investigation. Looking ahead, the integration of advanced imaging modalities, biomarkers, and artificial intelligence promises to revolutionize the diagnosis and treatment of coronary PE, ushering in a new era of personalized and precise cardiovascular care.

Background: Chronic inflammation is a constant phenomenon which accompanies the heart failure pathophysiology. In all phenotypes of heart failure, irrespective of the ejection fraction, there is a permanent low-grade activation and synthesis of proinflammatory cytokines. Many classes of anti-remodelling medication used in the treatment of chronic heart failure have been postulated to have an anti-inflammatory effect. Methods: This retrospective study enrolled 220 patients and focused on evaluating the effect of the most used active substances from these classes in reducing the level of inflammatory biomarkers (C reactive protein, erythrocyte sedimentation rate and fibrinogen) after initiation or up-titration. Our research is evaluating if this anti-inflammatory effect intensifies while raising the dose. The evaluation was performed at two visits with an interval between them of 6 months. Results: From the beta-blockers class, carvedilol showed a reduction in erythrocyte sedimentation rate (ESR), in low (6.25 mg, bi daily) and medium (12.5 mg, bi daily) doses. At the same time, sacubitril/valsartan showed a reduction in CRP levels. This effect was obtained only in the medium (49/51 mg, bi daily) and high (97/103 mg, bi daily) doses, with the maximum reduction being observed in the high dose. Conclusions: From the classes of medication evaluated, the study showed a significant reduction in ESR levels in the low and medium doses of carvedilol and a reduction in CRP values in the cases of medium and high doses of ARNI.

The beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on kidney function are well-known; however, their molecular mechanisms are not fully understood. We focused on 78-kDa glucose-regulated protein (GRP78) and its interaction with SGLT2 and integrin-β1 beyond the chaperone property of GRP78. In streptozotocin (STZ)-induced diabetic mouse kidneys, GRP78, SGLT2, and integrin-β1 increased in the plasma membrane fraction, while they were suppressed by canagliflozin. The altered subcellular localization of GRP78/integrin-β1 in STZ mice promoted epithelial mesenchymal transition (EMT) and fibrosis, which were mitigated by canagliflozin. High-glucose conditions reduced intracellular GRP78, increased its secretion, and caused EMT-like changes in cultured HK2 cells, which were again inhibited by canagliflozin. Urinary GRP78 increased in STZ mice, and in vitro experiments with recombinant GRP78 suggested that inflammation spread to surrounding tubular cells and that canagliflozin reversed this effect. Under normal glucose culture, canagliflozin maintained sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA) activity, promoted ER robustness, reduced ER stress response impairment, and protected proximal tubular cells. In conclusion, canagliflozin restored subcellular localization of GRP78, SGLT2, and integrin-β1 and inhibited EMT and fibrosis in DKD. In nondiabetic chronic kidney disease, canagliflozin promoted ER robustness by maintaining SERCA activity and preventing ER stress response failure, and it contributed to tubular protection.

Inflammation plays an essential role and is a common feature in the pathogenesis of many chronic diseases. The exact mechanisms through which sodium-glucose cotransporter-2 (SGLT2) inhibitors achieve their much-acclaimed clinical benefits largely remain unknown. In this review, we detail the systemic and tissue- or organ-specific anti-inflammatory effects of SGLT2 inhibitors using evidence from animal and human studies. We discuss the potential pathways through which SGLT2 inhibitors exert their anti-inflammatory effects, including oxidative stress, mitochondrial, and inflammasome pathways. Finally, we highlight the need for further investigation of the extent of the contribution of the anti-inflammatory effects of SGLT2 inhibition to improvements in cardiometabolic and renal outcomes in clinical studies.

Despite recent therapeutic advances, achieving optimal glycaemic control remains a challenge in managing Type 2 Diabetes (T2D). Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have emerged as effective treatments by promoting urinary glucose excretion. However, the full scope of their mechanisms extends beyond glycaemic control. At present, their immunometabolic effects remain elusive. To investigate the effects of SGLT2 inhibition or deletion, we compared the metabolic and immune phenotype between high fat diet-fed control, chronically dapagliflozin-treated mice and total-body SGLT2/Slc5a2 knockout mice. SGLT2 null mice exhibited superior glucose tolerance and insulin sensitivity compared to control or dapagliflozin-treated mice, independent of glycosuria and body weight. Moreover, SGLT2 null mice demonstrated physiological regulation of corticosterone secretion, with lowered morning levels compared to control mice. Systemic cytokine profiling also unveiled significant alterations in inflammatory mediators, particularly interleukin 6 (IL-6). Furthermore, unbiased proteomic analysis demonstrated downregulation of acute-phase proteins and upregulation of glutathione-related proteins, suggesting a role in the modulation of antioxidant responses. Conversely, IL-6 increased SGLT2 expression in kidney HK2 cells suggesting a role for cytokines in the effects of hyperglycemia. Collectively, our study elucidates a potential interplay between SGLT2 activity, immune modulation, and metabolic homeostasis.

Modifiable cardiovascular risk factors are high blood pressure, smoking, diabetes, sedentary lifestyle, obesity, and hypercholesterolemia.

To investigate the impact of sodium-glucose 2 co-transporter inhibitors (SGLT-2i) on modifiable cardiovascular risk factors in Romanian patients diagnosed with type 2 diabetes mellitus (T2DM).

A retrospective study was conducted on 200 Romanian patients with T2DM who were being treated with SGLT-2i, either Dapagliflozin or Empagliflozin. Collected data included demographic characteristics, such as weight, body mass index (BMI), fasting blood glucose (FBG), creatinine, glycated hemoglobin (HbA1c), abdominal circumference (AC), urine albumin-to-creatinine ratio (UACR), systolic blood pressure (SBP), diastolic blood pressure (DBP), C-reactive protein (CRP) and N-terminal pro b-type natriuretic peptide (NT-proBNP). The patients were observed for one year after being treated with SGLT-2i.

The mean value of FBG decreased from 180.00 mg% (IQR: 154.50-207.00) to 130.00 mg% (IQR: 117.50-150.00) (p < 0.001), and the mean of HbA1c values decreased from 8.40% (IQR: 7.98-9.15%) to 7.30% (IQR: 6.90-7.95%) (p < 0.001). We also obtained significant positive effects on body weight, i.e., the weight decreased from 90.50 kg (82.00-106.50) to 89.00 kg (77.50-100.00) (p = 0.018), BMI from 32.87 kg/m2 (29.24-36.45) to 31.00 kg/m2 (27.74-34.71) (p < 0.001) and AC from 107.05 (± 16.39) to 102.50 (± 15.11) (p = 0.042). The UACR decreased from 23.98 mg/g (19.76-36.85) to 19.39 mg/g (1.30-24.29) (p < 0.001). Initially, the median value for SBP was 140.00mmgHg (130.00-160.00), and for DBP was 80.00 mmgHg (72.00-90.00), and one year after treatment, the medium value was 120.00 mmgHg (115.50-130.00) for SBP (p < 0.001), and 72.00 mmgHg (70.00-78.00) for DBP (p < 0.001) The mean CRP values decreased from 68.00 mg/dL (56.25-80.25) to 34.00 mg/dL (28.12-40.12) (p < 0.001), and the mean NT-proBNP decreased from 146.00pg/mL (122.50-170.50) to 136.00 pg/mL (112.50-160.50) (p = 0.005).

Treatment with SGLT-2i in Romanian patients with T2DM has beneficial effects on modifiable cardiovascular risk factors.

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are increasingly recognized for their role in reducing the risk and improving the prognosis of heart failure (HF). However, the precise mechanisms involved remain to be fully delineated. Evidence points to their potential anti-inflammatory pathway in mitigating the risk of HF.

A two-sample, two-step Mendelian Randomization (MR) approach was employed to assess the correlation between SGLT-2 inhibition and HF, along with the mediating effects of inflammatory biomarkers in this relationship. MR is an analytical methodology that leverages single nucleotide polymorphisms as instrumental variables to infer potential causal inferences between exposures and outcomes within observational data frameworks. Genetic variants correlated with the expression of the SLC5A2 gene and glycated hemoglobin levels (HbA1c) were selected using datasets from the Genotype-Tissue Expression project and the eQTLGen consortium. The Genome-wide association study (GWAS) data for 92 inflammatory biomarkers were obtained from two datasets, which included 14,824 and 575,531 individuals of European ancestry, respectively. GWAS data for HF was derived from a meta-analysis that combined 26 cohorts, including 47,309 HF cases and 930,014 controls. Odds ratios (ORs) and 95% confidence interval (CI) for HF were calculated per 1 unit change of HbA1c.

Genetically predicted SGLT-2 inhibition was associated with a reduced risk of HF (OR 0.42 [95% CI 0.30-0.59], P < 0.0001). Of the 92 inflammatory biomarkers studied, two inflammatory biomarkers (C-X-C motif chemokine ligand 10 [CXCL10] and leukemia inhibitory factor) were associated with both SGLT-2 inhibition and HF. Multivariable MR analysis revealed that CXCL10 was the primary inflammatory cytokine related to HF (MIP = 0.861, MACE = 0.224, FDR-adjusted P = 0.0844). The effect of SGLT-2 inhibition on HF was mediated by CXCL10 by 17.85% of the total effect (95% CI [3.03%-32.68%], P = 0.0183).

This study provides genetic evidence supporting the anti-inflammatory effects of SGLT-2 inhibitors and their beneficial impact in reducing the risk of HF. CXCL10 emerged as a potential mediator, offering a novel intervention pathway for HF treatment.

Gout is the most common form of inflammatory arthritis worldwide and is characterized by painful recurrent flares of inflammatory arthritis that are associated with a transiently increased risk of adverse cardiovascular events. Furthermore, gout is associated with multiple cardiometabolic-renal comorbidities such as type 2 diabetes, chronic kidney disease and cardiovascular disease. These comorbidities, potentially combined with gout flare-related inflammation, contribute to persistent premature mortality in gout, independently of serum urate concentrations and traditional cardiovascular risk factors. Although better implementation of standard gout care could improve gout outcomes, deliberate efforts to address the cardiovascular risk in patients with gout are likely to be required to reduce mortality. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are approved for multiple indications owing to their ability to lower the risk of all-cause and cardiovascular death, hospitalizations for heart failure and chronic kidney disease progression, making them an attractive treatment option for gout. These medications have also been shown to lower serum urate concentrations, the causal culprit in gout risk, and are associated with a reduced risk of incident and recurrent gout, potentially owing to their purported anti-inflammatory effects. Thus, SGLT2 inhibition could simultaneously address both the symptoms of gout and its comorbidities.

Pancreatic carcinoma is a highly aggressive tumor that usually presents when it has already metastasized. Therapeutic options for cure remain scarce and rely on combination chemotherapy with limited sustainability. Diabetes is considered an important risk factor for the development of pancreatic cancer due to the production of proinflammatory cytokines, which result in increased cell proliferation. More than half of patients diagnosed with pancreatic cancer eventually develop diabetes due to the destruction of insulin-producing cells. The interlinkage of both diseases might identify a possible preventative strategy for reducing the incidence of pancreatic carcinoma. This study reviewed the recent literature on the association between pancreatic cancer risk and SGLT2 inhibitors, GLP-1 RA, DPP-4 inhibitors, and biguanides. There are mixed data regarding the relationship between GLP-1 RA and DPP-4 inhibitors and pancreatic cancer, with some trials suggesting that they might increase the risk. In contrast, studies have mostly revealed that SGLT2 inhibitors have an antiproliferative effect on various tumors, such as liver, pancreatic, prostate, bowel, lung, and breast carcinoma, which might be due to their mechanism of blockage of reabsorption of glucose by cells, lowering the amount of available glucose for the growth of tumor cells. Metformin, the first-line agent for diabetes, has also been shown to be associated with decreasing pancreatic cancer risk and improving prognosis in those who already have the disease. Dedicated trials are needed to further delineate the association of antidiabetic drugs with the risk of pancreatic cancer in the general population, as previous studies have mostly focused on diabetic patients.

Inflammation drives coronary artery disease and atherosclerosis implications. Lipoprotein entry, retention, and oxidative modification cause endothelial damage, triggering innate and adaptive immune responses. Recruited immune cells orchestrate the early atherosclerotic lesions by releasing proinflammatory cytokines, expediting the foam cell formation, intraplaque haemorrhage, secretion of matrix-degrading enzymes, and lesion progression, eventually promoting coronary artery syndrome via various inflammatory cascades. In addition, soluble mediators disrupt the dynamic anti- and prothrombotic balance maintained by endothelial cells and pave the way for coronary artery disease such as angina pectoris. Recent studies have established a relationship between elevated levels of inflammatory markers, including C-reactive protein (CRP), interleukins (IL-6, IL-1β), and tumour necrosis factor-alpha (TNF-α) with the severity of CAD and the possibility of future cardiovascular events. High-sensitivity C-reactive protein (hs-CRP) is a marker for assessing systemic inflammation and predicting the risk of developing CAD based on its peak plasma levels. Hence, understanding cross-talk interactions of inflammation, atherogenesis, and CAD is highly warranted to recalculate the risk factors that activate and propagate arterial lesions and devise therapeutic strategies accordingly. Cholesterol-inflammation lowering agents (statins), monoclonal antibodies targeting IL-1 and IL-6 (canakinumab and tocilizumab), disease-modifying antirheumatic drugs (methotrexate), sodium-glucose transport protein-2 (SGLT2) inhibitors, colchicine and xanthene oxidase inhibitor (allopurinol) have shown promising results in reducing inflammation, regressing atherogenic plaque and modifying the course of CAD. Here, we review the complex interplay between inflammatory, endothelial, smooth muscle and foam cells. Moreover, the putative role of inflammation in atherosclerotic CAD, underlying mechanisms and potential therapeutic implications are also discussed herein.

Anaemia, a condition characterized by low levels of haemoglobin, is frequently observed in patients with heart failure (HF). Guideline-directed medical therapy improves HF outcomes by using medications like beta blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, along with mineralocorticoid receptor antagonists and sodium-glucose cotransporter 2 inhibitors. In this study, we aimed to review the pathophysiology of anaemia in patients with HF and present the current evidence regarding the relationship between the main recommended medications for these patients and haemoglobin levels. The authors conducted a comprehensive search in the medical literature for relevant original clinical articles in which the four pharmacological pillars of HF were given to the patients; we, then, assessed whether the association of use of these medications and haemoglobin level or development of anaemia was provided. These common medications have been shown in the literature that may exacerbate or ameliorate anaemia. Besides, it has been shown that even in the case that they result in the development of anaemia, their use is associated with positive effects that outweigh this potential harm. The literature also suggests that among patients receiving medications with negative effects on the level of haemoglobin, there was no difference in the rate of mortality between anaemic and non-anaemic patients when both were on treatment for anaemia; this point highlights the importance of the detection and treatment of anaemia in these patients. Further research is needed to explore these relationships and identify additional strategies to mitigate the risk of anaemia in this population.

Chronic low-grade inflammation is involved in coronary atherosclerosis progression whereas recent research efforts suggest that preventative methods should be tailored to the "residual inflammatory risk". As such, modalities for the early identification of the risk have to be investigated.

We performed a systematic review and meta-analysis according to the PRISMA guidelines. Any study that presented the prognostic value of high sensitivity troponin (hs-cTn) of vascular inflammation in stable patients without known cardiac heart disease was considered to be potentially eligible. The Medline (PubMed) database was searched up to April 22, 2021. The main endpoint was the difference in c-index (Δ[c-index]) with the use of hs-cTn for major adverse cardiovascular events (MACEs), cardiovascular and all-cause mortality. We calculated I2 to test heterogeneity.

In total, 44 studies and 112,288 stable patients without known coronary heart disease were included in this meta-analysis. The mean follow-up duration of the whole cohort was 6.8 ± 1.1 years. 77,004 (68.5%) of the patients presented at low cardiovascular risk while 35,284 (31.5%) in high. The overall pooled estimate of Δ[c-index] for MACE was 1.4% (95%CI: 0.7-2.1, I2=0%) and for cardiovascular death 1.3% (95%CI: 0.3-2.3, I2=0%). Finally, the overall pooled estimate of Δ[c-index] for all-cause mortality was 3% (95%CI: 1.9-3.9, I2=86%), while high heterogeneity was observed between the studies.

The predictive usefulness of changes in hs-cTn measures in stable individuals with either high or low cardiovascular risk, demonstrates that assessing vascular inflammation in addition to clinical risk factors enhances risk prediction for cardiovascular events and allcause mortality. Further prospective studies are necessary to confirm these findings and assist clinical decision-making regarding the most optimal prevention strategy.

Large-scale clinical trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrate proteinuria-reducing effects in diabetic kidney disease, even after treatment with renin-angiotensin inhibitors. The precise mechanism for this favorable effect remains unclear. This prospective open-label single-arm study investigated factors associated with a reduction in proteinuria after SGLT2i administration.

Patients with type 2 diabetes (T2DM) who had glycated hemoglobin (HbA1c) levels ≥ 6.5% despite dietary and/or oral hypoglycemic monotherapy were recruited and administered the recommended daily dose of SGLT2i for 4 months. Dual primary outcomes were changes in the urine albumin-to-creatinine ratio (uACR) and urine liver-type fatty acid-binding protein (L-FABP)-to-creatinine ratio (uL-FABPCR) at month 4 from baseline. Changes in kidney injury, inflammation, and oxidative stress biomarkers were investigated as secondary endpoints to examine the effects of this treatment on the kidney. The correlation between renal outcomes and clinical indicators, including circulating tumor necrosis factor receptors (TNFR) 1 and 2, was evaluated using univariate and multivariate analyses.

Participants (n = 123) had a mean age of 64.1 years (SD 13.4), with 50.4% being male. The median BMI was 25.8 kg/m2 (interquartile range (IQR) 23.1-28.9), and the median HbA1c level was 7.3% (IQR 6.9-8.3). After SGLT2i administration, the uACR declined from 19.2 mg/gCr (IQR 7.1-48.7) to 13.3 mg/gCr (IQR 7.5-31.6), whereas the uL-FABPCR was not influenced. In univariate analysis, the change in log-transformed uACR due to SGLT2i administration showed a positive correlation with the change in serum TNFR1 level (R = 0.244, p < 0.01). Multivariate regression analysis, including confounding factors, showed that the changes in serum TNFR1 level were independently associated with the changes in the log-transformed uACR (independent t = 2.102, p < 0.05).

After the 4-month SGLT2i administration, decreased albuminuria level was associated with decreased serum TNFR level in patients with T2DM.

UMIN000031947.

Sodium-glucose co-transporters (SGLTs) in the kidneys play a pivotal role in glucose reabsorption. Several clinical and population-based studies revealed the beneficial effects of SGLT2 inhibition on hypertension. Recent work from our lab provided significant new insight into the role of SGLT2 inhibition in a non-diabetic model of salt-sensitive hypertension, Dahl salt-sensitive (SS) rats. Dapagliflozin (Dapa) blunted the development of salt-induced hypertension by causing glucosuria and natriuresis without changes in the Renin-Angiotensin-Aldosterone System. However, our initial study used male SS rats only, and the effect of SGLT2 inhibitors on hypertension in females has not been studied. Therefore, the goal of this study was to determine whether SGLT2 inhibition alters blood pressure and kidney function in female Dahl SS rats. The result showed that administration of Dapa for 3 weeks prevented the progression of salt-induced hypertension in female rats, similar to its effects in male SS rats. Diuresis and glucose excretion were significantly increased in Dapa-treated rats. SGLT2 inhibition also significantly attenuated kidney but not heart fibrosis. Despite significant effects on blood pressure, Dapa treatment caused minor changes to electrolyte balance and no effects on kidney and heart weights were observed. Our data suggest that SGLT2 inhibition in a non-diabetic model of salt-sensitive hypertension blunts the development of salt-induced hypertension independent of sex.

Aortic stenosis (AS) is the most frequent valvular heart disease among the older individuals. Current guidelines indicate intervention for patients with symptomatic or fast progressive severe AS and asymptomatic patients with a reduced left ventricular (LV) ejection fraction by 50%. Interestingly, myocardial damage may have already happened by the time symptoms appear or LV function deteriorates. Serum biomarkers can be an early indicator to show LV function decline and AS progression even before clinical symptom onset. Studies have shown that cardiac biomarkers have prognostic value in patients with AS. Hence, cardiac biomarkers can be helpful in determining the optimum time to intervene. Transcatheter aortic valve replacement is a less invasive alternative to conventional surgical aortic valve replacement. The elevation of cardiac biomarkers at discharge has been associated with 2-year mortality after transcatheter aortic valve replacement. The correlation between biomarkers and AS-associated morbidity and mortality is an area to explore further. The authors of this review article have discussed the role of cardiac biomarkers in patients with AS for better risk stratification and identification of patients who would benefit from early intervention.

There are previous epidemiological studies reporting associations between antibiotic use and psychiatric symptoms. Antibiotic-induced gut dysbiosis and alteration of microbiota-gut-brain axis communication has been proposed to play a role in this association. In this systematic review and meta-analysis, we reviewed published articles that have presented results on changes in cognition, emotion, and behavior in rodents (rats and mice) after antibiotic-induced gut dysbiosis. We searched three databases-PubMed, Web of Science, and SCOPUS to identify such articles using dedicated search strings and extracted data from 48 articles. Increase in anxiety and depression-like behavior was reported in 32.7 and 40.7 percent of the study-populations, respectively. Decrease in sociability, social novelty preference, recognition memory and spatial cognition was found in 18.1, 35.3, 26.1, and 62.5 percent of the study-populations, respectively. Only one bacterial taxon (increase in gut Proteobacteria) showed statistically significant association with behavioral changes (increase in anxiety). There were no consistent findings with statistical significance for the potential biomarkers [Brain-derived neurotrophic factor (BDNF) expression in the hippocampus, serum corticosterone and circulating IL-6 and IL-1β levels]. Results of the meta-analysis revealed a significant association between symptoms of negative valence system (including anxiety and depression) and cognitive system (decreased spatial cognition) with antibiotic intake (p < 0.05). However, between-study heterogeneity and publication bias were statistically significant (p < 0.05). Risk of bias was evaluated to be high in the majority of the studies. We identified and discussed several reasons that could contribute to the heterogeneity between the results of the studies examined. The results of the meta-analysis provide promising evidence that there is indeed an association between antibiotic-induced gut dysbiosis and psychopathologies. However, inconsistencies in the implemented methodologies make generalizing these results difficult. Gut microbiota depletion using antibiotics may be a useful strategy to evaluate if and how gut microbes influence cognition, emotion, and behavior, but the heterogeneity in methodologies used precludes any definitive interpretations for a translational impact on clinical practice.

Atherosclerosis, a chronic inflammatory disease characterized by arterial plaque accumulation, remains a significant global health challenge. In recent years, inflammasomes, the intracellular multiprotein complexes crucial for initiating innate immune responses, have emerged as key players in atherosclerosis pathophysiology. This review article aims to provide a comprehensive overview of the current understanding of inflammasome activation and its impact on atherosclerosis development and progression. We explore the intricate interplay between traditional cardiovascular risk factors and inflammasome activation, leading to the perpetuation of inflammatory cascades that drive plaque formation and instability. The review focuses on the molecular mechanisms underlying inflammasome activation, including the role of pattern recognition receptors and cytokines in this process. Moreover, we discuss the contribution of inflammasomes to endothelial dysfunction, foam cell formation, and vascular inflammation. Additionally, recent advances in therapeutic strategies targeting inflammasomes are examined, including pharmacological agents and potential immunomodulatory approaches. By collating and analyzing the current evidence, this review provides valuable insights into the potential of inflammasome-targeted therapies for atherosclerosis management and treatment. Understanding the pivotal role of inflammasomes in atherosclerosis pathophysiology offers promising prospects for developing effective and personalized therapeutic interventions that can mitigate the burden of this prevalent cardiovascular disorder and improve patient outcomes.