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Background & aim: SGLT2 inhibitors (SGLT2i) improve hepatic steatosis in patients with type 2 diabetes mellitus (T2DM) and MASLD. We aimed to investigate the impact of SGLT2i on the incidence of liver-related events and extrahepatic cancer compared to DPP4 inhibitors (DPP4i) in patients with T2DM and suspected MASLD using a medical claims database in Japan. Methods: We conducted a retrospective study using a Japanese medical claims database. Among patients with T2DM who were prescribed SGLT2i or DPP4i (n = 1,628,656), patients with suspected MASLD were classified into SGLT2i (n = 4204) and DPP4i (n = 4204) groups. Effects of SGLT2i on the following outcomes were compared to DPP4i: (1) changes in HbA1c and ALT levels after 6 months, (2) changes in hepatic fibrosis index, and (3) the incidence of liver-related events/extrahepatic cancer over 12 months. Results: After 6 months, DPP4i significantly decreased HbA1c levels compared to SGLT2i. In contrast, SGLT2i significantly decreased ALT levels compared to DPP4i. SGLT2i significantly decreased FIB-4 index compared to DPP4i over 12 months. Although no significant difference was observed in the incidence of overall liver-related events between the two groups, SGLT2i significantly reduced the incidence of esophageal varices (HR 0.12, 95%CI 0.01–0.95, P = 0.044). Moreover, SGLT2i significantly suppressed the incidence of extrahepatic cancer (HR 0.50, 95%CI 0.30–0.84, P = 0.009) compared to DPP4i. Conclusion: SGLT2i was more beneficial than DPP4i in improving the hepatic inflammation and fibrosis indices. Moreover, SGLT2i suppressed the incidence of esophageal varices and extrahepatic cancer compared to DPP4i. SGLT2i may suppress life-threatening events in patients with T2DM and suspected MASLD. [ABSTRACT FROM AUTHOR]

Background: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) represent a high-risk heart failure population with continued unmet therapeutic needs. Sodium–glucose co-transporter 2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with heart failure across the whole spectrum of ejection fraction, and first evidence regarding their safety and effectiveness in patients with ATTR-CM is arising. This study investigates the association between SGLT2i therapy and clinical outcomes in these patients. Methods: This is an analysis of a prospective registry conducted at a referral centre for hypertrophic cardiomyopathies including 116 patients with confirmed ATTR-CM. Fifty-one patients (44%) were treated with SGLT2i while 65 patients (56%) remained SGLT2i-naïve. Results: During a median follow-up of 2.6 (1.7–3.7) years, 38 patients (33%) died, of whom 11 patients (9%) received SGLT2i treatment and 27 patients (23%) were treatment-naïve. SGLT2i therapy was significantly associated with lower mortality (HR 0.457, 95%CI 0.227–0.922, p = 0.029). This association persisted after adjusting for age and sex (HR 0.479, 95%CI 0.235–0.977, p = 0.043) and after additional adjustment for eGFR, NT-proBNP, LVEF, and concomitant therapy with tafamidis (HR 0.328, 95%CI 0.141–0.760, p = 0.009). However, when potential immortal time bias was considered, this association lost statistical significance (HR 1.075, 95%CI 0.524–2.206, p = 0.843). No significant associations between SGLT2i therapy and worsening heart-failure hospitalization or cardiovascular mortality were observed. Conclusions: In crude analysis, SGLT2i therapy associates with better survival in patients with ATTR-CM. However, after adjustment for immortal time, this association becomes statistically insignificant. Hence, to draw final conclusions on the effectiveness of SGLT2i therapy in these patients, a randomized controlled trial is warranted. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is a prevalent disease in the general population and also a well-established risk factor for the development of ischemic stroke. Patients who have been diagnosed with diabetes have a 20% higher risk for developing ischemic stroke in comparison to non-diabetic individuals. The aim of the current systematic review is to provide the latest evidence regarding the association between antidiabetic treatment and the prevention of ischemic stroke. Methods: A comprehensive search in scientific literature databases PUBMED, COCHRANE, and SCOPUS was conducted. The studies that were deemed as eligible for this review were those that examined the clinical benefits of therapeutic strategies in terms of preventing ischemic strokes. Results: A total of 32 studies met the established selection criteria. The included studies showed that pioglitazone treatment significantly reduced the risk for recurrent stroke in patients with DM. Furthermore, in the context of primary prevention, the improvement in glycemic control after treatment with the glucagon-like peptide-1 receptor agonists (GLP-1RA) semaglutide and dulaglutide was associated with a reduction in the risk of ischemic stroke in diabetic subjects. Metformin monotherapy may reduce stroke risk, while dipeptidyl peptidase 4 inhibitors, sodium-glucose co-transporter 2 inhibitors, and insulin do not seem to affect the incidence of stroke. Conclusions: The findings of the present systematic review suggest that pioglitazone and GLP-1RA may decrease the risk of stroke. Further studies are needed to provide additional data regarding the preventive effect of novel antidiabetic drugs, such as dual glucose-dependent insulinotropic polypeptide/GLP-1RA agents, on stroke. [ABSTRACT FROM AUTHOR]

Early-stage (stage 1–3) chronic kidney disease (CKD) has an asymptomatic presentation such that most people with CKD are unaware of their disease status and remain undiagnosed. CKD is associated with multiple long-term conditions (MLTC), or multimorbidity, the most common of these being cardiovascular disease, hypertension, and type 2 diabetes. Primary care practitioners (PCPs) are crucial in the early identification and management of patients with CKD. For individuals at high risk of CKD, measurements of estimated glomerular filtration rate, urine albumin–creatinine ratio, and blood pressure should be obtained regularly and recorded in a timely manner. The importance of lifestyle changes in the prevention and management of CKD should also be highlighted. A recent addition to the treatment of CKD in people with and without type 2 diabetes has been the recommendation by clinical practice guidelines of a sodium–glucose co-transporter 2 (SGLT2) inhibitor alongside a renin–angiotensin–aldosterone system inhibitor as foundational therapy. SGLT2 inhibitors prevent CKD progression and reduce fatal and non-fatal kidney and cardiovascular events, hospitalization for heart failure, and all-cause mortality, and they have a favorable safety and tolerability profile. However, uptake has been slow, particularly in people with CKD without type 2 diabetes. A multifaceted approach is required to ensure that people with CKD receive optimal kidney protection. Measures to raise awareness of the importance of early identification and intervention include local/national campaigns via social media and practice-based education; clinical education programs; integration of clinical decision support tools into electronic health records; detection programs built around electronic health records; and good interdisciplinary communication. PCPs at the forefront of multidisciplinary care are best placed to implement the evidence-based clinical practice CKD guidelines for lifestyle modification and guideline-directed medical therapy. Plain Language Summary: Chronic kidney disease, or CKD, affects about one in ten adults worldwide. Results from many real-world studies show that early identification and treatment of CKD is crucial to prevent the disease from getting worse. However, because CKD can have no symptoms in its early stages, it is often not diagnosed. Many people with CKD are therefore unaware that they have it. People with CKD are likely to have other long-term health issues as well, including cardiovascular disease, hypertension and diabetes. Primary care practitioners are best placed to offer holistic, patient-centered care to those with CKD, and are the frontline in identifying and managing the risk factors for chronic disease. Primary care practitioners may advise people with CKD on lifestyle changes, such as diet and exercise, as well as helping them understand what treatments are available. Sodium–glucose co-transporter 2 inhibitors have shown strong kidney-protective effects in clinical trials, and recently updated clinical guidelines recommend their use as foundational therapy alongside more established treatments of CKD. These treatments should be prescribed to people with CKD whether they have diabetes or not. For people at high risk of CKD, primary care practitioners should regularly obtain and record measurements of kidney function and blood pressure. Public and primary care practitioner awareness and education, the use of clinical decision support tools, and good communication between healthcare professionals are all important to drive change in primary care and improve the early identification and management of CKD. [ABSTRACT FROM AUTHOR]

Abstract Aims The trials upon which recommendations for the use of cardiac resynchronization therapy (CRT) in heart failure used optimal medical therapy (OMT) before sodium‐glucose co‐transporter 2 inhibitors (SGLT2i). Moreover, the SGLT2i heart failure trials included only a small proportion of participants with CRT, and therefore, it remains uncertain whether SGLT2i should be considered part of OMT prior to CRT. Methods and results We compared electrocardiogram (ECG) and echocardiographic responses to CRT as well as hospitalization and mortality rates in consecutive patients undergoing implantation at a large tertiary centre between January 2019 to June 2022 with and without SGLT2i treatment. Three hundred seventy‐four participants were included aged 74.0 ± 11.5 years (mean ± standard deviation), with a left ventricular ejection fraction (LVEF) of 31.8 ± 9.9% and QRS duration of 161 ± 29 ms. The majority had non‐ischaemic cardiomyopathy (58%) and were in NYHA Class II/III (83.6%). These characteristics were similar between patients with (n = 66) and without (n = 308) prior SGLT2i treatment. Both groups demonstrated similar evidence of response to CRT in terms of QRS duration shortening, and improvements in LVEF, left ventricular end‐diastolic inner‐dimension (LVIDd) and diastolic function (E/A and e/e′). While there was no difference in rates of hospitalization (for heart failure or overall), mortality was significantly lower in patients treated with SGLT2i compared with those who were not (6.5 vs. 16.6%, P = 0.049). Conclusions We observed an improvement in mortality in patients undergoing CRT prescribed SGLT2i compared with those not prescribed SGLT2i, despite similar degrees of reverse remodelling. The authors recommend starting SGLT2i prior to CRT implantation, where it does not delay implantation.

Abstract Background and Aims Sodium-glucose co-transporter 2 (SGLT2) inhibitors have beneficial effects in heart failure (HF), including reverse remodelling, but the mechanisms by which these benefits are conferred are unclear. Inflammation is implicated in the pathophysiology of heart failure (HF) and there are some pre-clinical data suggesting that SGLT2 inhibitors may reduce inflammation. There is however a lack of clinical data. The aim of our study was to investigate whether improvements in cardiac remodelling caused by dapagliflozin in individuals with type 2 diabetes (T2D) and left ventricular hypertrophy (LVH) were associated with its effects on inflammation. Methods We measured C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin 6 (IL-6), and interleukin 10 (IL-10) and neutrophil-to-lymphocyte ratio (NLR) in plasma samples of 60 patients with T2D and left ventricular hypertrophy (LVH) but without symptomatic HF from the DAPA-LVH trial in which participants were randomised dapagliflozin 10 mg daily or placebo for 12 months and underwent cardiac magnetic resonance imaging (CMR) at baseline and end of treatment. The primary analysis was to investigate the effect of dapagliflozin on inflammation and to assess the relationships between changes in inflammatory markers and LV mass and global longitudinal strain (GLS) and whether the effect of dapagliflozin on LV mass and GLS was modulated by baseline levels of inflammation. Results Following 12 months of treatment dapagliflozin significantly reduced CRP compared to placebo (mean difference of -1.96; 95% CI -3.68 to -0.24, p = 0.026). There were no significant statistical changes in other inflammatory markers. There were modest correlations between improvements in GLS and reduced inflammation (NLR (r = 0.311), IL-1β (r = 0.246), TNF-α (r = 0.230)) at 12 months. Conclusions Dapagliflozin caused a significant reduction in CRP compared to placebo. There were correlations between reductions in inflammatory markers including IL-1β and improvements in global longitudinal strain (but not reduced LV mass). Reductions in systemic inflammation might play a contributory role in the cardiovascular benefits of dapagliflozin. Trial registration Clinicaltrials.gov NCT02956811 (06/11/2016).

A recent study published in the European Heart Journal investigated the effects of sodium-glucose co-transporter 2 inhibitors (SGLT2is) on human myocardial slices. The researchers utilized a miniaturized model of living myocardial slices and performed single-nucleus RNA sequencing to analyze the molecular events elicited by SGLT2is in the diseased human myocardium. The study found that SGLT2is had cell-type-specific effects, including preventing adverse cardiac remodeling and improving contractile function. The findings suggest that SGLT2is may have cardiovascular benefits in heart failure patients. However, further research is needed to fully understand the effects of SGLT2is on the proteome and functional level. [Extracted from the article]

Atrial fibrillation (AF) is a common arrhythmic complication in cancer patients and can be exacerbated by traditional cytotoxic and targeted anticancer therapies. Increased incidence of AF in cancer patients is independent of confounding factors, including preexisting myocardial arrhythmogenic substrates, type of cancer, or cancer stage. Mechanistically, AF is characterized by fast unsynchronized atrial contractions with rapid ventricular response, which impairs ventricular filling and results in various symptoms such as fatigue, chest pain, and shortness of breath. Due to increased blood stasis, a consequence of both cancer and AF, concern for stroke increases in this patient population. To compound matters, cardiotoxic anticancer therapies themselves promote AF; thereby exacerbating AF morbidity and mortality in cancer patients. In this review, we examine the relationship between AF, cancer, and cardiotoxic anticancer therapies with a focus on the shared molecular and electrophysiological mechanisms linking these disease processes. We also explore the potential role of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in the management of anticancer-therapy-induced AF. • Atrial Fibrillation (AF) is prevalent among active cancer patients and survivors. • Several classes of anticancer drug therapies also increase AF risk. • Preexisting and cancer-related cardiac remodeling contributes to AF development. • Oxidative stress, inflammation, and ionic alterations have been documented. • Emerging data suggests a role for SGLT2i in management of anticancer-induced AF. [ABSTRACT FROM AUTHOR]

The global burden of chronic kidney disease (CKD) is high and increasing. Early diagnosis and intervention are key to improve outcomes. Single-nephron glomerular hyperfiltration is an early pathophysiologic manifestation of CKD that may result in absolute glomerular hyperfiltration, i.e. a high glomerular filtration rate (GFR), or be associated with normal or low GFR because of nephron loss (relative glomerular hyperfiltration). Even though compensatory glomerular hyperfiltration may contribute to maintain kidney function after the loss of kidney mass, the associated increased glomerular capillary pressure and glomerular and podocyte size drive podocyte loss, albuminuria and proximal tubular overload, contributing to CKD progression. In this regard, all kidney protective drugs in clinical use so far, from renin–angiotensin system blockers to mineralocorticoid receptor blockers to sodium–glucose co-transporter 2 inhibitors to tolvaptan, induce an early dip in glomerular filtration that is thought to represent reversal of hyperfiltration. As glomerular hyperfiltration may be present early in the course of kidney disease, its recognition may provide an effective intervention window that may predate current criteria based on high albuminuria or loss of GFR. Nevertheless, there is no diagnostic method with high sensitivity and specificity to identify single-nephron glomerular hyperfiltration, except when it leads to obvious absolute glomerular hyperfiltration, as observed in the early stages of diabetic kidney disease when nephron mass is still preserved. We now review the concept of glomerular hyperfiltration as an indicator of CKD risk, including definitions, challenges in diagnosis and evaluation, underlying pathophysiological mechanisms, potential therapeutic approaches and unanswered questions. [ABSTRACT FROM AUTHOR]

Key Clinical Message: This is the first case report in which computed tomography (CT) images of a patient with emphysematous pyelonephritis (EPN) capture the time course of emphysema from onset to resolution through conservative treatment. To re‐evaluate EPN, including refractory urinary tract infections, CT scans after 72 h might be helpful. [ABSTRACT FROM AUTHOR]

Aims: The trials upon which recommendations for the use of cardiac resynchronization therapy (CRT) in heart failure used optimal medical therapy (OMT) before sodium‐glucose co‐transporter 2 inhibitors (SGLT2i). Moreover, the SGLT2i heart failure trials included only a small proportion of participants with CRT, and therefore, it remains uncertain whether SGLT2i should be considered part of OMT prior to CRT. Methods and results: We compared electrocardiogram (ECG) and echocardiographic responses to CRT as well as hospitalization and mortality rates in consecutive patients undergoing implantation at a large tertiary centre between January 2019 to June 2022 with and without SGLT2i treatment. Three hundred seventy‐four participants were included aged 74.0 ± 11.5 years (mean ± standard deviation), with a left ventricular ejection fraction (LVEF) of 31.8 ± 9.9% and QRS duration of 161 ± 29 ms. The majority had non‐ischaemic cardiomyopathy (58%) and were in NYHA Class II/III (83.6%). These characteristics were similar between patients with (n = 66) and without (n = 308) prior SGLT2i treatment. Both groups demonstrated similar evidence of response to CRT in terms of QRS duration shortening, and improvements in LVEF, left ventricular end‐diastolic inner‐dimension (LVIDd) and diastolic function (E/A and e/e′). While there was no difference in rates of hospitalization (for heart failure or overall), mortality was significantly lower in patients treated with SGLT2i compared with those who were not (6.5 vs. 16.6%, P = 0.049). Conclusions: We observed an improvement in mortality in patients undergoing CRT prescribed SGLT2i compared with those not prescribed SGLT2i, despite similar degrees of reverse remodelling. The authors recommend starting SGLT2i prior to CRT implantation, where it does not delay implantation. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular-kidney-metabolic (CKM) syndrome is highly prevalent in the US Medicare population and is projected to increase further. Sodium-glucose co-transporter 2 inhibitors have indications in chronic kidney disease (CKD), heart failure (HF), and type 2 diabetes (T2D), providing protective efficacy across conditions within CKM syndrome. The objective of this study was to develop a model to extrapolate key outcomes observed in pivotal clinical trials to the US Medicare population, and to assess the potential direct cost offsets associated with dapagliflozin therapy. Methods: All US 2022 Medicare beneficiaries (≥ 65 years of age) eligible to receive dapagliflozin were estimated according to drug label indication and Medicare enrollment and claims data. Incidence of key outcomes from the dapagliflozin clinical program were modelled over a 4-year time horizon based on patient-level data with CKD, HF, and T2D. Published cost data of relevant clinical outcomes were used to calculate direct medical care cost-offset associated with treatment with dapagliflozin. Results: In a population of 13.1 million patients with CKM syndrome, treatment with dapagliflozin in addition to historical standard of care (hSoC) versus hSoC alone led to fewer incidents of HF-related events (hospitalization for HF, 613,545; urgent HF visit, 98,896), renal events (kidney failure, 285,041; ≥ 50% sustained decline in kidney function, 375,137), and 450,355 fewer deaths (of which 225,346 and 13,206 incidences of cardiovascular and renal death were avoided). In total this led to medical care cost offsets of $99.3 billion versus treatment with hSoC only (dapagliflozin plus hSoC, $310.3 billion; hSoC, $211.0 billion). Conclusion: By extrapolating data from trials across multiple indications within CKM syndrome, this broader perspective shows that considerable medical care cost offsets may result through attenuated incidence of clinical events in CKD, T2D, and HF populations if treated with dapagliflozin in addition to hSoC over a 4-year time horizon. Graphical abstract available for this article. [ABSTRACT FROM AUTHOR]

Abstract Heart failure poses a global health challenge affecting millions of individuals, and access to guideline-directed medical therapy is often limited. This limitation is frequently attributed to factors such as drug availability, slow adoption, clinical inertia, and delayed diagnosis. Despite international recommendations promoting the use of guideline-directed medical therapy for heart failure management, personalized approaches are essential in settings with resource constraints. In India, crucial treatments like angiotensin II receptor blocker neprilysin inhibitors and sodium-glucose co-transporter 2 inhibitors are not fully utilized despite their established safety and efficacy. To address this issue, an expert consensus involving 150 specialists, including cardiologists, nephrologists, and endocrinologists, was convened. They deliberated on patient profiles, monitoring, and adverse side effects and provided tailored recommendations for guideline-directed medical therapy in heart failure management. Stressing the significance of early initiation of guideline-directed medical therapy in patients with heart failure, especially with sodium-glucose co-transporter 2 inhibitors, the consensus also explored innovative therapies like vericiguat. To improve heart failure outcomes in resource-limited settings, the experts proposed several measures, including enhanced patient education, cardiac rehabilitation, improved drug access, and reforms in healthcare policies.

Heart failure poses a global health challenge affecting millions of individuals, and access to guideline-directed medical therapy is often limited. This limitation is frequently attributed to factors such as drug availability, slow adoption, clinical inertia, and delayed diagnosis. Despite international recommendations promoting the use of guideline-directed medical therapy for heart failure management, personalized approaches are essential in settings with resource constraints. In India, crucial treatments like angiotensin II receptor blocker neprilysin inhibitors and sodium-glucose co-transporter 2 inhibitors are not fully utilized despite their established safety and efficacy. To address this issue, an expert consensus involving 150 specialists, including cardiologists, nephrologists, and endocrinologists, was convened. They deliberated on patient profiles, monitoring, and adverse side effects and provided tailored recommendations for guideline-directed medical therapy in heart failure management. Stressing the significance of early initiation of guideline-directed medical therapy in patients with heart failure, especially with sodium-glucose co-transporter 2 inhibitors, the consensus also explored innovative therapies like vericiguat. To improve heart failure outcomes in resource-limited settings, the experts proposed several measures, including enhanced patient education, cardiac rehabilitation, improved drug access, and reforms in healthcare policies. [ABSTRACT FROM AUTHOR]

Introduction: Prediabetes is a state of subclinical glycemic impairment, bridging normal glucose tolerance and diabetes. Globally, over 30% of individuals exhibit prediabetic conditions, with a significant proportion progressing to diabetes. Prediabetes augments risks of various diseases including cardiovascular and kidney disease. While interventions like lifestyle changes have shown promise in diabetes prevention, their long-term sustainability is challenging. Alternative pharmacological treatments, such as acarbose and metformin, have demonstrated efficacy in certain populations. Sodium-glucose co-transporter 2 inhibitors, a novel class of glucose-lowering agents, have shown potential benefits for heart and kidney health in patients with diabetes. This research aims to evaluate the effectiveness and safety of dapagliflozin in individuals with prediabetes, elucidating its potential role in diabetes prevention strategies. Research Design and Methods: This prospective trial is being conducted at Peking University Third Hospital. A total of 240 participants with prediabetes will be enrolled and randomly divided into two groups: one receiving dapagliflozin (10 mg/day) with lifestyle education, and the other with lifestyle education alone over a 12-week duration (with male/female = 1:1 in each group). Anthropometric, clinical and laboratory tests, including body mass index, waist circumference, fasting blood glucose, oral glucose tolerance test, insulin, lipid profile, liver and kidney function, sperm quality, will be conducted at the onset and conclusion of the trial. For adherence monitoring, participants will receive phone follow-ups at week 4 and week 8. The primary outcome is the change in 2-h plasma glucose during an oral glucose tolerance test over the study duration. Secondary outcomes encompass changes in various health metrics, including body mass index, lipid profiles, and liver function. Planned Outcomes: The proposed study is set to refine diabetes prevention strategies on the basis of its potential benefits observed in patients with diabetes. Conclusions: This will be the first randomized controlled trial to evaluate the safety and effectiveness of sodium-glucose co-transporter 2 inhibitors compared with lifestyle education for individuals with prediabetes. Trial Registration: ClinicalTrials.gov identifier NCT05914857 (registered 24 July 2023). [ABSTRACT FROM AUTHOR]

Purpose of Review: Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in disease-modifying therapy, the mainstay of treatment for congestion—loop diuretics—has remained largely unchanged for 50 years. In these two articles (part I: loop diuretics and part II: combination therapy), we will review the history of diuretic treatment and current trial evidence for different diuretic strategies and explore potential future directions of research. Recent Findings: We will assess recent trials, including DOSE, TRANSFORM, ADVOR, CLOROTIC, OSPREY-AHF, and PUSH-AHF, and assess how these may influence current practice and future research. Summary: There are few data on which to base diuretic therapy in clinical practice. The most robust evidence is for high-dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF, yet this is not reflected in guidelines. There is an urgent need for more and better research on different diuretic strategies in patients with HF. [ABSTRACT FROM AUTHOR]

The main goals of the pharmacological treatment of Heart failure with reduced ejection fraction (HFrEF) are the reduction of mortality and the prevention of hospitalizations. However, other outcomes such as improvements in cardiac remodeling and clinical status, functional capacity and quality of life, should be taken into account. Also, given the significant inter-individual and intra-individual variability of HF, and the fact that patients usually present with comorbidities, an appropriate treatment for HFrEF should exert a clinical benefit in most patient profiles irrespective of their characteristics or the presence of comorbidities, while providing organ protection beyond the cardiovascular system. The aim of this narrative review is to determine which are the proven effects of the guideline-directed treatments for HFrEF on five key clinical outcomes: cardiovascular mortality and hospitalization due to HF, sudden death, reverse cardiac remodeling, renal protection and evidence in hospitalized patients. Publications that fulfilled the pre-established selection criteria were selected and reviewed. Renin-angiotensin system (RAS) inhibitors, namely angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), sodium-glucose co-transporter 2 inhibitors (SGLT2i) show a benefit in terms of mortality and hospitalization rates. ARNI, BB, and MRA have demonstrated a significant positive effect on the incidence of sudden death. ARB, ARNI, BB and SGLT2i have been associated with clear benefits in reverse cardiac remodeling. Additionally, there is consistent evidence of renal protection from ARB, ARNI, and SGLT2i in renal protection and of benefits for hospitalized patients from ARNI and SGLT2i. In conclusion, the combination of drugs that gather most beneficial effects in HFrEF, beyond cardiovascular mortality and hospitalization, would be ideally pursued.

Key Clinical Message This is the first case report in which computed tomography (CT) images of a patient with emphysematous pyelonephritis (EPN) capture the time course of emphysema from onset to resolution through conservative treatment. To re‐evaluate EPN, including refractory urinary tract infections, CT scans after 72 h might be helpful.

Abstract Background The 2022 Canadian Cardiovascular Society (CCS) cardiorenal guideline provided clinical recommendations on sodium-glucose co-transport 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) use. Since then, additional trials of relevance for SGLT2i have been published. This update re-evaluates the clinical recommendations for using SGLTi and their indirect comparison with existing evidence on GLP-1RA as compared to the standard of care to reduce cardiorenal morbidity and mortality. Methods We updated our existing search and screening of the literature from September 2021 to April 2023 for randomized controlled trials of SGLT2i and GLP-1RA with placebo control. We conducted risk of bias assessment, data extraction and updated our meta-analysis of studies with similar interventions and components. The certainty of the evidence was determined using GRADE. Results Evidence from three new trials and additional results from an updated existing trial on SGLT2i met our inclusion criteria after an updated search. Across all the included studies, the total sample size was 151,023 adults, with 90,943 in SGLT2i trials and 60,080 in GLP-1 RA trials. The mean age ranged from 59.9 to 68.4 years. Compared with standard care, the use of SGLT2i and GLP-1 RA showed significant reductions in the outcomes of cardiovascular (CV) mortality (14% & 13%), any-cause mortality (12% & 12%), major adverse CV events (MACE) (11% & 14%), heart failure (HF) hospitalization (30% & 9%), CV death or HF hospitalization (23% & 11%), and kidney composite outcome (32% & 22%). In participants with T2D, both classes demonstrated significant cardiorenal protection. But, only GLP-1RA showed a reduction in non-fatal stroke (16%) and only SGLT2i showed a reduction in HF hospitalization (30%) in this population of people living with T2D. Conclusions This updated and comprehensive meta-analysis substantiates and strengthens the clinical recommendations of the CCS cardiorenal guidelines.

Abstract Aims Sodium‐glucose co‐transporter 2 (SGLT2) inhibitors have shown potential therapeutic benefits in heart failure (HF). However, data on their real‐world usage and benefits in acute decompensated heart failure (ADHF) are limited. Methods and results We conducted a post hoc analysis of real‐world data from 1108 patients with ADHF admitted to Nihon University Itabashi Hospital (Tokyo, Japan) between 2018 and 2022. Patients were divided into two groups based on the prescription of SGLT2 inhibitors during hospitalization: an SGLT2 inhibitor group (SGLT2i group) (n = 289) and a non‐SGLT2i group (n = 819). The primary endpoints were death and rehospitalization for HF after discharge. The median age was 76 [interquartile range (IQR): 66, 83] years, and 732 patients (66%) were male. Data showed an increasing trend in the prescription of SGLT2 inhibitors since 2021. During a median follow‐up period of 366 days (IQR: 116, 614), 458 (41.3%) patients reached the primary endpoint. The Kaplan–Meier analysis showed that the SGLT2i group had a significantly lower rate of composite events than the non‐SGLT2i group, both overall (log‐rank test, P

Background and aims: In the past few years, some reports have shown that serum chloride concentration is a more powerful prognostic predictor than serum sodium levels in heart failure (HF). Elevated Na/Cl ratio has shown to be independently associated with all-cause death in acute HF. We evaluated changes in serum chloride concentrations and Na/Cl ratio in correlation with various clinical factors during 12 months of follow-up in patients in whom SGLT2is were initiated as part of HF therapy. Patients and methods: This was a prospective observational study conducted at University Hospital Dubrava and involving patients with HF. We included 241 participants between May 2021 and April 2023. All data were obtained before the introduction of SGLT2is, and the same parameters were obtained at 6 and 12 months of follow-up as well. Results: The results show that higher chloride concentration at both 6 and 12 months is an independent predictor of lower NT-proBNP levels. The chloride concentrations did not differ significantly between these groups in the follow-up period. There were no statistically significant differences in the Na/Cl ratio at different timepoints. The presence of cardiovascular risk factors did not significantly affect the increase in chloride concentration. Conclusions: Our results suggest that hypochloremia could be a potentially modifiable risk factor, given the influence of SGLT2is on chloride concentration, but also an ominous sign of a poor outcome in patients with HF. We believe that the determination of chloride concentrations should become routine in the monitoring of patients with HF.

Aim: Sodium‐glucose co‐transporter 2 inhibitors and mineralocorticoid receptor antagonists reduce albuminuria and the risk of kidney failure. The aim of this study was to investigate the effects of both agents alone and in combination on markers of the glomerular endothelial glycocalyx and tubular function. Methods: This post‐hoc analysis utilized data of the ROTATE‐3 study, a randomized cross‐over study in 46 adults with chronic kidney disease and urinary albumin excretion ≥100 mg/24 h, who were treated for 4 weeks with dapagliflozin, eplerenone or its combination. The effects of dapagliflozin, eplerenone and the combination on outcome measures such as heparan sulphate, neuro‐hormonal markers and tubular sodium handling were assessed with mixed repeated measures models. Results: The mean percentage change from baseline in heparan sulphate after 4 weeks treatment with dapagliflozin, eplerenone or dapagliflozin‐eplerenone was −34.8% (95% CI −52.2, −10.9), −5.9% (95% CI −32.5, 31.3) and −28.1% (95% CI −48.4, 0.1) respectively. The mean percentage change from baseline in plasma aldosterone was larger with eplerenone [38.9% (95% CI 2.8, 87.7)] and dapagliflozin‐eplerenone [32.2% (95% CI −1.5, 77.4)], compared with dapagliflozin [−12.5% (95% CI −35.0, 17.8)], respectively. Mean percentage change from baseline in copeptin with dapagliflozin, eplerenone or dapagliflozin‐eplerenone was 28.4% (95% CI 10.7, 49.0), 4.2% (95% CI −10.6, 21.4) and 23.8% (95% CI 6.6, 43.9) respectively. Dapagliflozin decreased proximal absolute sodium reabsorption rate by 455.9 mmol/min (95% CI −879.2, −32.6), while eplerenone decreased distal absolute sodium reabsorption rate by 523.1 mmol/min (95% CI −926.1, −120.0). Dapagliflozin‐eplerenone decreased proximal absolute sodium reabsorption [−971.0 mmol/min (95% CI −1411.0, −531.0)], but did not affect distal absolute sodium reabsorption [−9.2 mmol/min (95% CI −402.0, 383.6)]. Conclusions: Dapagliflozin and eplerenone exert different effects on markers of glomerular and tubular function supporting the hypothesis that different mechanistic pathways may account for their kidney protective effects. [ABSTRACT FROM AUTHOR]

Heart failure (HF) affects an estimated 6 million American adults, and the prevalence continues to increase, driven in part by the aging of the population and by increases in the prevalence of diabetes. In recent decades, improvements in the survival of patients with HF have resulted in a growing number of individuals living longer with HF. HF and its comorbidities are associated with substantial impairments in physical functioning, emotional well-being, and quality of life, and also with markedly increased rates of morbidity and mortality. As a result, the management of patients with HF has a substantial economic impact on the health care system, with most costs arising from hospitalization. Clinicians have an important role in helping to reduce the burden of HF through timely diagnosis of HF as well as increasing access to effective treatments to minimize symptoms, delay progression, and reduce hospital admissions. Prevention and early diagnosis of HF will play a fundamental role in efforts to reduce the large and growing burden of HF. Recent advances in pharmacotherapies for HF have the potential to radically change the management of HF, offering the possibility of improved survival and quality of life for patients. [ABSTRACT FROM AUTHOR]

This chapter is intended to provide a plain language overview of heart failure suitable for non-medical professionals, including patients and caregivers, and a patient perspective on living with heart failure. [ABSTRACT FROM AUTHOR]

Cardiovascular outcomes trials of sodium-glucose co-transporter-2 (SGLT2) inhibitors have demonstrated consistent signals of benefit in terms of both prevention and treatment of heart failure (HF), in patients with and without type 2 diabetes (T2D). In response to growing evidence of the benefits of SGLT2 inhibitors, including increased survival, reduced hospitalizations and improved patient-reported symptoms, functional status, and quality of life, the treatment landscape for HF has evolved. Importantly, these agents have also demonstrated safety and tolerability in individuals with HF across the spectrum of left ventricular ejection fraction, with improvements in clinical and patient-reported outcomes occurring as early as days to weeks after treatment initiation. For patients with heart failure with reduced ejection fraction (HFrEF), SGLT2 inhibitors are now increasingly recognized as foundational disease-modifying therapy. An updated joint guideline from the American College of Cardiology and American Heart Association now recommends including SGLT2 inhibitors for patients with HF across the spectrum of ejection fraction, irrespective of the presence of diabetes, and regardless of background therapy (Class 1 recommendation for HFrEF, Class 2a recommendation for HF with mildly reduced ejection fraction [HFmrEF] and HF with preserved ejection fraction [HFpEF]). The European Society of Cardiology also include a Class I recommendation to use SGLT2 inhibitors for patients with HFrEF to reduce the risk of hospitalization for HF and CV death, irrespective of T2D status. This chapter reviews published clinical trial data about the efficacy and safety of SGLT2 inhibitors among patients with HFrEF, HFpEF, and patients hospitalized for HF. [ABSTRACT FROM AUTHOR]

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as an important approach for the treatment of heart failure in patients with or without diabetes. Although the precise mechanisms underpinning their clinical impact remain incompletely resolved, mechanistic studies and insights from major clinical trials have demonstrated the impact of SGLT2 inhibitors on numerous cardio-renal-metabolic pathways of relevance to heart failure with preserved ejection fraction (HFpEF), which, in the contemporary era, constitutes approximately half of all patients with heart failure. Despite rates of morbidity and mortality that are commensurate with those of heart failure with reduced ejection fraction, disease-modifying therapies have comparatively been severely lacking. As such, HFpEF remains among the greatest unmet needs in cardiovascular medicine. Within the past decade, HFpEF has been established as a highly integrated disorder, involving not only the cardiovascular system, but also the lungs, kidneys, skeletal muscle, and adipose tissue. Given their multisystem impact, SGLT2i offer unique promise in addressing the complex pathophysiology of HFpEF, and in recent randomized controlled trials, were shown to significantly reduce heart failure events and cardiovascular death in patients with HFpEF. Herein, we discuss several proposed mechanisms of clinical benefit of SGLT2i in HFpEF. [ABSTRACT FROM AUTHOR]

Aims: Sodium‐glucose co‐transporter 2 (SGLT2) inhibitors have shown potential therapeutic benefits in heart failure (HF). However, data on their real‐world usage and benefits in acute decompensated heart failure (ADHF) are limited. Methods and results: We conducted a post hoc analysis of real‐world data from 1108 patients with ADHF admitted to Nihon University Itabashi Hospital (Tokyo, Japan) between 2018 and 2022. Patients were divided into two groups based on the prescription of SGLT2 inhibitors during hospitalization: an SGLT2 inhibitor group (SGLT2i group) (n = 289) and a non‐SGLT2i group (n = 819). The primary endpoints were death and rehospitalization for HF after discharge. The median age was 76 [interquartile range (IQR): 66, 83] years, and 732 patients (66%) were male. Data showed an increasing trend in the prescription of SGLT2 inhibitors since 2021. During a median follow‐up period of 366 days (IQR: 116, 614), 458 (41.3%) patients reached the primary endpoint. The Kaplan–Meier analysis showed that the SGLT2i group had a significantly lower rate of composite events than the non‐SGLT2i group, both overall (log‐rank test, P < 0.001) and in the following left ventricular ejection fraction (LVEF) subgroups: HF with reduced ejection fraction (EF) (n = 413), HF with mildly reduced EF (n = 226), and HF with preserved EF (n = 466) (log‐rank test; P = 0.044, P = 0.013, and P = 0.001, respectively). Furthermore, patients starting SGLT2 inhibitors during hospitalization had a significantly lower rate of composite events than those not using SGLT2 inhibitors (log‐rank test, P < 0.001). This association was also significant in the LVEF subgroups (P = 0.005, P = 0.032, and P = 0.004, respectively). Conclusions: The prescription and initiation of SGLT2 inhibitors during hospitalization are associated with improved post‐discharge outcomes in patients with ADHF, irrespective of LVEF. [ABSTRACT FROM AUTHOR]

AimsRecent trials have evaluated sodium-glucose co-transporter 2 inhibitors in patients with heart failure (HF). We sought to assess the robustness of findings from these trials using the fragility index (FI).Methods and resultsFragility index is defined as the minimum number of patients that must be moved from the 'non-event' to the 'event' group to turn a statistically significant result to non-significant. In addition to FI, fragility quotient [(FQ); FI divided by the sample size] was calculated to assess the proportion of events that must be moved to change the significance. For statistically non-significant outcomes, reverse fragility index (RFI) and reverse fragility quotient (RFQ) were calculated. Robustness of findings after pooling data from all three trials was also assessed. A robust reduction in first HF hospitalization or cardiovascular mortality was seen with dapagliflozin (FI = 62 and FQ = 0.013), empagliflozin (FI = 50 and FQ = 0.013), and sotagliflozin (FI = 60 and FQ = 0.049). Dapagliflozin nominally improved all-cause and cardiovascular mortality, with modest FI (n = 8 and 5) and FQ (0.002 and 0.001). Empagliflozin and sotagliflozin did not demonstrate statistically significant reductions in all-cause mortality, with modest RFI (empagliflozin: RFI = 26 and RFQ = 0.007; sotagliflozin: RFI = 6 and RFQ = 0.005). A similar trend was seen with cardiovascular mortality (empagliflozin: RFI = 24 and RFQ = 0.006; sotagliflozin: RFI = 7 and RFQ = 0.006). Upon meta-analysis, the result for first HF hospitalization or cardiovascular mortality was robust (FI = 95 and FQ = 0.010). The reductions in all-cause (FI = 12 and FQ = 0.001) and cardiovascular mortality (FI = 9 and FQ = 0.001), while statistically significant, were fragile.ConclusionImprovement in the composite outcome of first HF hospitalization or cardiovascular death was highly concordant and robust across sodium-glucose co-transporter 2 inhibitor trials. In contrast, secondary endpoints of all-cause and cardiovascular mortality were statistically fragile, underscoring the need to power trials for mortality to fully understand the benefit of therapies on fatal events.

Aim. To identify the features of the course of COVID-19 in patients with type 2 diabetes mellitus (T2DM), depending on the intake of hypoglycemic therapy at the prehospital stage, in conjunction with the functional state of the kidneys. Materials and methods. A retrospective analysis of 291 case histories of patients with COVID-19 and T2DM hospitalized in the infection department of Semashko Regional Clinical Hospital from January to December 2021, including the main clinical and laboratory parameters. Results. Among hospitalized patients with COVID-19, patients with T2DM had a higher mortality rate. An analysis of the case histories of deceased patients with COVID-19 and T2DM showed that at admission, body mass index (BMI), C-reactive protein, and creatinine were higher than those of survivors and amounted to BMI – 33 [30; 39] and 33 [28; 36] kg/m3; p=0.039, C-reactive protein – 77 [47.5; 106.0] and 57 [27.0; 89.0] mg/l; p=0.015, in terms of creatinine level – 89 [70.0; 144.0] and 82 [66.0; 101.0] µmol/l; p=0.039, respectively. It was found that in the second week of hospitalization in the group of deceased patients with COVID-19 and T2DM, the creatinine level was statistically significantly higher than in surviving patients and amounted to 94.5 [71.5; 141.0] and 72.5 [57.0; 88.0] µmol/L; p0.001, respectively. The probability of death in hospitalized patients with type 2 COVID-19 and T2DM depended on BMI and creatinine levels at the second week of hospitalization. Patients with prehospital correction of hyperglycemia dipeptidyl peptidase-4 inhibitors (iDPP-4)/ glucagon-like peptide-1 receptor agonists (agGLP-1)/ sodium-glucose co-transporter 2 inhibitors (iSGLT-2) had significantly lower creatinine levels at week 2 of hospitalization. Conclusion. In patients with moderate to severe COVID-19 with concomitant T2DM, special attention should be paid to the combination of high BMI and creatinine in the second week of hospitalization, which is a prognostically unfavorable predictor of death in such patients.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have recently been recommended as a foundational therapy for patients with heart failure (HF) and reduced ejection fraction (HFrEF) because of their favourable effects on mortality, clinical events and quality of life. While clinical practice guidelines have recommended dapagliflozin or empagliflozin in all patients with HFrEF, or sotagliflozin in those with HFrEF and concomitant diabetes, the timing and practical integration of these drugs in clinical practice is less well defined. We propose that these drugs are candidates for early, upfront administration to patients with newly diagnosed HFrEF and for patients hospitalized with HF. Growing evidence has established early benefits, with clinically meaningful reductions in clinical events that reach statistical significance within days to weeks, following dapagliflozin, empagliflozin or, in diabetic patients, sotagliflozin initiation. Secondly, although major clinical trials have tested these drugs in patients already receiving background HF therapy, secondary analyses showed that their efficacy is independent of that. Third, SGLT2 inhibitors are generally safe and well tolerated, with clinical trial data reporting minimal effects on blood pressure, glycaemia-related adverse events, and no excess in acute kidney injury. Rather, they exert renal protective effects and reduce risk of hyperkalaemia, properties that favour initiation, tolerance and persistence of renin-angiotensin system inhibitors and mineralocorticoid receptor antagonists. This review supports the early initiation of dapagliflozin and empagliflozin (or sotagliflozin limited to patients with diabetes) to rapidly improve clinical outcome and quality of life of HFrEF patients.

Abstract Background We conducted a systematic review and meta-analysis to summarize the available literature and comprehensively appraise the renal profiles of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in Japanese patients with type 2 diabetes mellitus (T2DM). Methods The electronic databases MEDLINE, Ichushi-web, and ClinicalTrials.gov were searched for studies without language restrictions from their inception until 20 July 2023 and CENTRAL until 21 September 2021. Studies were included if they were double-masked randomized controlled trials (RCTs) (1) including Japanese patients with T2DM aged > 18 years who received SGLT2i or a placebo, (2) reporting at least one renal outcome of serum creatinine or the estimated glomerular filtration rate (eGFR), and (3) with a follow-up of > 12 weeks. Cross-over and open label trials were excluded. The risk of bias based on the Cochrane risk-of-bias tool for randomized trials (RoB 2) was appraised. We computed the weighed mean difference with 95%CI for each renal outcome and used a random-effects model (inverse variance method). Results We ultimately retrieved 13 RCTs including 2687 individuals in our review. The durations of RCTs ranged between 12 and 104 weeks. Only one trial had a longer duration of more than one year. Ten out of 13 RCTs reported serum creatinine, while nine included eGFR. Serum creatinine and eGFR were slightly worse with SGLT2i than with a placebo [mean difference 0.01 (95%CI 0.00 to 0.02) mg/dL, p = 0.002, mean difference − 1.30 (95%CI -2.23 to -0.37) mL/min/1.73 m2, p = 0.006, respectively]. Merged results revealed insignificant heterogeneity (I2

Heart failure (HF) and chronic kidney disease (CKD) are associated with high mortality. In both disorders, impaired iron homeostasis, mostly in the form of a functional iron deficiency, is a frequent co-morbidity. In HF, functional iron deficiency and management by i.v. iron supplementation have been proven to affect both prognosis and functional capacity. In the same context, iron supplementation is routine for the adequate management of renal anemia in CKD. In numerous recent studies in HF and in CKD, sodium–glucose transporter 2 (SGLT2) inhibitor treatment has been proven to significantly reduce mortality. Furthermore, the same trials showed that these drugs alleviate iron deficiency and anemia. These effects of SGLT2 inhibitors may be due to an amelioration of inflammation with reduced interleukin-6 (IL-6) and to an enhancement of autophagy with increased sirtuin 1 (SIRT1), both associated with modified production of hepcidin and enhanced ferritinophagy. However, the exact pathogenic basis of the beneficial SGLT2 inhibitor action is not fully elucidated. Nevertheless, effects on iron homeostasis might be a potential explanatory mechanism for the powerful SGLT2 inhibitors' cardiovascular and renal outcome benefits. In addition, the interaction between iron supplementation and SGLT2 inhibitors and its potential impact on prognosis remains to be clarified by future studies. This review represents a significant effort to explore the complex relationships involved, seeking to elucidate the intricate mechanisms by which SGLT2 inhibitors influence iron homeostasis. [ABSTRACT FROM AUTHOR]

Objective: Results from large placebo-controlled randomized trials in patients with heart failure with mid-range ejection fraction (HFmrEF) and HF with preserved EF (HFpEF) have become available recently. This article discusses results of these clinical trials. Data Sources: Peer-reviewed articles were identified from MEDLINE (1966 to December 31, 2022) using search terms dapagliflozin, empagliflozin, SGLT-2Is, HFmrEF, and HFpEF. Study Selection and Data Extraction: Eight completed, pertinent clinical trials were included. Data Synthesis: EMPEROR-Preserved, and DELIVER demonstrated that empagliflozin and dapagliflozin reduce CV death and heart failure hospitalization (HHF) in patients with HFmrEF and HFpEF, with/without diabetes when added to a standard heart failure (HF) regimen. The benefit is primarily due to reduction in HHF. Additional data from post hoc analyses of trials of dapagliflozin, ertugliflozin, and sotagliflozin suggest that these benefits may be a class effect. Benefits appear greatest in patients with left ventricular ejection fraction 41% up to about 65%. Relevance to Patient Care and Clinical Practice: While many pharmacologic treatments have been proven to reduce mortality and improve cardiovascular (CV) outcomes in people with HFmrEF and HF with reduced EF (HFrEF), there are few therapy which improve CV outcome in people with HFpEF. SGLT-2I become one of the first class of pharmacologic agent that can be used to reduce HHF and CV mortality. Conclusion: Studies showed that empagliflozin and dapagliflozin reduce the combined risk of CV death or HHF in patients with HFmrEF and HFpEF when added to a standard HF regimen. Given that benefit has now been demonstrated across the spectrum of HF, SGLT-2Is should be considered one of the standard HF pharmacotherapy. [ABSTRACT FROM AUTHOR]

Aims Treatment with sodium-glucose co-transporter 2 (SGLT2)-inhibitors reduces the risk of cardiovascular disease and mortality, but the mechanism is unclear. We hypothesized that a functional genetic variant in solute carrier family 5 member 2 (SLC5A2), known to be associated with familial renal glucosuria, would mimic pharmacological SGLT2-inhibition, and thus provide an opportunity to examine potential mediators of the effects on lower risk of cardiovascular disease and mortality. Methods and results We examined 112 712 individuals from the Copenhagen City Heart Study and Copenhagen General Population Study (CCHS + CGPS), 488 687 from the UK Biobank, and 342 499 from FinnGen, genotyped for SLC5A2 rs61742739, c.1961A > G; p.(Asn654Ser). The 2.0% heterozygotes and 0.01% homozygotes were pooled as carriers and compared with the 98% non-carriers. First, we examined the risk of cardiovascular disease and mortality; second, whether carrying the variant was associated with potential mediators of the effect; and third, whether identified potential mediators could explain the observed reduced risk of cardiovascular disease and mortality. In the CCHS + CGPS, carriers vs. non-carries had a 31% lower risk of heart failure, 21% lower risk of myocardial infarction, 16% lower risk of ischaemic heart disease, and 22% lower risk of all-cause mortality. Corresponding values in meta-analyses of the three studies combined were lower risk by 10%, 6%, 6%, and 10%, respectively. The SLC5A2 rs61742739 variant was not associated with a risk of ischaemic stroke or cardiovascular mortality. Of the lower risks observed in CCHS + CGPS, lower plasma glucose mediated 2.0%(P = 0.004) on heart failure, 3.1%(P = 0.09) on myocardial infarction, 4.1%(P = 0.02) on ischaemic heart disease, and 6.0%(P = 0.39) on all-cause mortality; corresponding values in the UK Biobank were 2.9%(P = 0.70), 1.5%(P = 0.77), 4.1%(P = 0.23), and 3.1%(P = 0.21), respectively. Conclusion A functional genetic variant in SLC5A2 , mimicking SGLT2-inhibition, was associated with a lower risk of heart failure, myocardial infarction, ischaemic heart disease, and all-cause mortality. These effects were at most minimally mediated through lower plasma glucose. [ABSTRACT FROM AUTHOR]

Background: Type 2 Diabetes Mellitus (T2DM) patients are exposed to a 7.5 times higher risk of hypoglycemia while fasting during Ramadan. Relevant diabetes guidelines prioritize the use of SGLT2 inhibitors over other classes. There is a great need to enrich data on their safe and effective use by fasting patients at greater risk of hypoglycemia. Therefore, this study aims to assess the safety and tolerability of Empagliflozin in T2DM Muslim patients during Ramadan. Methodology: A prospective cohort study was conducted for adult Muslim T2DM patients. Patients who met the inclusion criteria were categorized into two sub-cohorts based on Empagliflozin use during Ramadan (Control versus Empagliflozin). The primary outcomes were the incidence of hypoglycemia symptoms and confirmed hypoglycemia. Other outcomes were secondary. All patients were followed up to eight weeks post-Ramadan. A propensity score (PS) matching and Risk Ratio (RR) were used to report the outcomes. Results: Among 1104 patients with T2DM who were screened, 220 patients were included, and Empagliflozin was given to 89 patients as an add-on to OHDs. After matching with PS (1:1 ratio), the two groups were comparable. The use of other OHDs, such as sulfonylurea, DPP4 inhibitors, and Biguanides, was not statistically different between the two groups. The risk of hypoglycemia symptoms during Ramadan was lower in patients who received Empagliflozin than in the control group (RR 0.48 CI 0.26, 0.89; p-value = 0.02). Additionally, the risk of confirmed hypoglycemia was not statistically significant between the two groups (RR 1.09 CI 0.37, 3.22; p-value = 0.89). Conclusion: Empagliflozin use during Ramadan fasting was associated with a lower risk of hypoglycemia symptoms and higher tolerability. Further randomized control trials are required to confirm these findings.

Background: We conducted a systematic review and meta-analysis to summarize the available literature and comprehensively appraise the renal profiles of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in Japanese patients with type 2 diabetes mellitus (T2DM). Methods: The electronic databases MEDLINE, Ichushi-web, and ClinicalTrials.gov were searched for studies without language restrictions from their inception until 20 July 2023 and CENTRAL until 21 September 2021. Studies were included if they were double-masked randomized controlled trials (RCTs) (1) including Japanese patients with T2DM aged > 18 years who received SGLT2i or a placebo, (2) reporting at least one renal outcome of serum creatinine or the estimated glomerular filtration rate (eGFR), and (3) with a follow-up of > 12 weeks. Cross-over and open label trials were excluded. The risk of bias based on the Cochrane risk-of-bias tool for randomized trials (RoB 2) was appraised. We computed the weighed mean difference with 95%CI for each renal outcome and used a random-effects model (inverse variance method). Results: We ultimately retrieved 13 RCTs including 2687 individuals in our review. The durations of RCTs ranged between 12 and 104 weeks. Only one trial had a longer duration of more than one year. Ten out of 13 RCTs reported serum creatinine, while nine included eGFR. Serum creatinine and eGFR were slightly worse with SGLT2i than with a placebo [mean difference 0.01 (95%CI 0.00 to 0.02) mg/dL, p = 0.002, mean difference − 1.30 (95%CI -2.23 to -0.37) mL/min/1.73 m2, p = 0.006, respectively]. Merged results revealed insignificant heterogeneity (I2 < 30%). Conclusion: These results suggest that SGLT2i slightly worsens serum creatinine and eGFR in Japanese patients with T2DM. However, since the durations of most RCTs were short, the effects of eGFR in particular may be transient. Further evidence is needed from rigorous studies that focus on renal outcomes with a longer duration to confirm the present results. [ABSTRACT FROM AUTHOR]

Purpose: To investigate trends in SGLT2i and GLP-1RA use in Australia in the era of increased evidence of their cardiovascular benefits. Methods: We used national dispensing claims for a 10% random sample of Australians to estimate the number of prevalent and new users (no dispensing in the prior year) of SGLT2i or GLP-1RA per month from January 2014 to July 2022. We assessed prescriber specialty and prior use of other antidiabetic and cardiovascular medicines as a proxy for evidence of type 2 diabetes (T2D) and cardiovascular conditions, respectively. Results: We found a large increase in the number of prevalent users (216-fold for SGLT2i; 11-fold for GLP-1RA); in July 2022 approximately 250,000 Australians were dispensed SGLT2i and 120,000 GLP-1RA. Most new users of SGLT2i or GLP-1RA had evidence of both T2D and cardiovascular conditions, although from 2022 onwards, approximately one in five new users of SGLT2i did not have T2D. The proportion of new users initiating SGLT2i by cardiologists increased after 2021, reaching 10.0% of initiations in July 2022. Among new users with evidence of cardiovascular conditions, empagliflozin was the most commonly prescribed SGLT2i, while dulaglutide or semaglutide was the most common GLP-1RA. Conclusion: SGLT2i and GLP-1RA use is increasing in Australia, particularly in populations with higher cardiovascular risk. The increased use of SGLT2i among people without evidence of T2D suggests that best-evidence medicines are adopted in Australia across specialties, aligning with new evidence and expanding indications. [ABSTRACT FROM AUTHOR]

Abstract Aims Heart failure (HF) is the most frequent cause of hospital admission among patients 65 years or older. Patients hospitalized for acutely decompensated chronic HF and ‘de novo’ acute heart failure (AHF) continue to experience unacceptably high post‐discharge readmission and mortality rates. Methods and results Until recently, trials had failed to improve outcome in patients with AHF irrespective of ejection fraction with exception of sodium‐glucose co‐transporter 2 inhibitors (SGLT2i) that improved clinical outcomes in patients hospitalized for AHF in the Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart Failure (EMPULSE) and in the Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure (SOLOIST‐WHF) trials. Conclusions This document reviews the potential utility of SGLT2i in patients hospitalized for AHF.

Type 2 Diabetes Mellitus (T2DM) patients are exposed to a 7.5 times higher risk of hypoglycemia while fasting during Ramadan. Relevant diabetes guidelines prioritize the use of SGLT2 inhibitors over other classes. There is a great need to enrich data on their safe and effective use by fasting patients at greater risk of hypoglycemia. Therefore, this study aims to assess the safety and tolerability of Empagliflozin in T2DM Muslim patients during Ramadan. A prospective cohort study was conducted for adult Muslim T2DM patients. Patients who met the inclusion criteria were categorized into two sub-cohorts based on Empagliflozin use during Ramadan (Control versus Empagliflozin). The primary outcomes were the incidence of hypoglycemia symptoms and confirmed hypoglycemia. Other outcomes were secondary. All patients were followed up to eight weeks post-Ramadan. A propensity score (PS) matching and Risk Ratio (RR) were used to report the outcomes. Among 1104 patients with T2DM who were screened, 220 patients were included, and Empagliflozin was given to 89 patients as an add-on to OHDs. After matching with PS (1:1 ratio), the two groups were comparable. The use of other OHDs, such as sulfonylurea, DPP4 inhibitors, and Biguanides, was not statistically different between the two groups. The risk of hypoglycemia symptoms during Ramadan was lower in patients who received Empagliflozin than in the control group (RR 0.48 CI 0.26, 0.89; p-value = 0.02). Additionally, the risk of confirmed hypoglycemia was not statistically significant between the two groups (RR 1.09 CI 0.37, 3.22; p-value = 0.89). Empagliflozin use during Ramadan fasting was associated with a lower risk of hypoglycemia symptoms and higher tolerability. Further randomized control trials are required to confirm these findings. [ABSTRACT FROM AUTHOR]

The role of Sodium-glucose co-transporter 2 inhibitors (SGLT2i) in heart failure is established. Early data also suggests their favorable role in patients with acute coronary syndromes, but more evidence is still needed. In this dual center, double-blinded randomized controlled trial, non-diabetic patients (N = 100) who presented with anterior ST- elevation myocardial infarction (STEMI) & had undergone successful primary percutaneous coronary intervention, but their left ventricular ejection fraction was below 50%, were randomized to dapagliflozin 10 mg or a placebo once daily. The primary endpoint was a change in cardiac function assessed by N-terminal pro-Brain Natriuretic Peptide – NT-proBNP measured at baseline & 12 weeks post the cardiac event &/or echocardiographic parameters (left ventricular ejection fraction, left ventricular diastolic dimension & left ventricular mass index) assessed at baseline, 4-weeks & 12-weeks post the cardiac event. From October 2021 to April 2022, 100 patients were randomized. The mean drop of NT- proBNP in the study group was more significant compared to the control group by 10.17% (95% CI: −3.28–19.67, p -value 0.034). In addition, the decrease in the left ventricular mass index (LV mass index) was also significant in the study group compared to the control group by 11.46% (95% CI: −19.37 to −3.56, p-value 0.029). Dapagliflozin seems to have a role in preventing left ventricular dysfunction & maintaining cardiac function following anterior ST-elevation myocardial infarction. More Large-scale trials need to be done to confirm these findings further. This trial is locally registered at the National Heart Institute, Cairo – Egypt, and Faculty of Medicine, Ain Shams University, with reference numbers CTN1012021 & MS-07/2022, respectively. It is also registered retrospectively at the US National Institutes of Health (ClinicalTrial.gov) with identifier number: NCT05424315 – June 16th,2022. • In-hospital initiation of dapagliflozin after acute anterior myocardial infarction may have a role in maintaining cardiac function and preventing heart failure post-MI. • Patients taking dapagliflozin over a placebo had significantly lower levels of NT-proBNP and lower left ventricular mass index. [ABSTRACT FROM AUTHOR]

The kidney has a prominent role in maintaining glucose homeostasis by using glucose as a metabolic substrate. This occurs by generating glucose through gluconeogenesis, and by reuptaking filtered glucose through the sodium–glucose cotransporters SGLT1 and SGLT2 located in the proximal tubule. In recent studies, the administration of sodium–glucose cotransporters inhibitors demonstrated that inhibition of renal glucose reabsorption significantly reduces adverse renal events and heart failure exacerbations, in type 2 diabetic patients with and without cardiovascular damage as well as in advanced chronic kidney disease and heart failure patients with reduced ejection fraction with and without diabetes. The benefit was consistent throughout the different investigated clinical conditions, ameliorating overall patient outcome. The efficacy of sodium glucose cotransporters inhibitors was prominently linked to the limitation of renal damage as highlighted by the significant reduction on global mortality achieved in the studies investigating diabetic and not diabetic populations with advanced chronic kidney disease. Both studies were halted at the interim analysis because of unquestionable evidence of treatment benefit. In current review, we examine the role of SGLT2 and SGLT1 in the regulation of renal glucose reabsorption in health and disease and the effect of SGLT2 inhibition on clinical outcomes of populations with different cardiovascular conditions investigated with large-scale outcome trials. [ABSTRACT FROM AUTHOR]

Introduction. The development of heart failure is closely associated with the appearance of life threatening arrhythmias, which are often a terminal event for these patients. An analysis of randomized clinical trials of inhibitors of sodium-glucose cotransporter type 2 indicates the clinically significant potential of these drugs as agents with antiarrhythmic properties. However, at the moment the full mechanism by which this effect can be realized is still not fully understood.Aim. To evaluate the effect of empagliflozin on the transmembrane calcium currents and the intracellular calcium transients on isolated ventricular cardiomyocytes of mice under conditions of normoglycemia.Materials and methods. In the experiment, ventricular cardiomyocytes were isolated from 12 outbred male mice. 2 groups were formed: group № 1 – control ventricular cardiomyocytes; group № 2 – ventricular cardiomyocytes after two hours incubation with 5 µmol/L empagliflozin solution. Transmembrane calcium currents were recorded and intracellular calcium transients were assessed.Results and discussion. Incubation of ventricular cardiomyocytes with empagliflozin significantly increased ICa current density and accelerated Ca2+ temporal dynamics. The amplitude of the Ca2+ wave and the rate of rise and decay were increased and the duration of the Ca2+ wave was shortened.Conclusion. The result of the experiment indicates that empagliflozin is able to modulate Ca2+-dependent mechanism of the excitation-contraction-coupling, enhancing and accelerating Ca2+ release into cytoplasm and reuptake. This presumably can optimize, namely reduce the time of systole and enhance it, which may be one of the important elements in the manifestation of empagliflozin antiarrhythmic properties.

Abstract Background Characteristics of patients using newer 2nd and 3rd line antidiabetic drugs in a real-world setting are poorly understood. We described the characteristics of new users of sodium-glucose co-transporter-2 inhibitors (SGLT-2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in Canada and the United Kingdom (UK) between 2016 and 2018. Methods We conducted a multi-database cohort study using administrative health databases from 7 Canadian provinces and the UK Clinical Practice Research Datalink. We assembled a base cohort of antidiabetic drug users between 2006 and 2018, from which we constructed 3 cohorts of new users of SGLT-2i, DPP-4i, and GLP-1 RA between 2016 and 2018. Results Our cohorts included 194,070 new users of DPP-4i, 166,722 new users of SGLT-2i, and 27,719 new users of GLP-1 RA. New users of GLP-1 RA were more likely to be younger (mean ± SD: 56.7 ± 12.2 years) than new users of DPP-4i (67.8 ± 12.3 years) or SGLT-2i (64.4 ± 11.1 years). In Canada, new users of DPP-4i were more likely to have a history of coronary artery disease (22%) than new users of SGLT-2i (20%) or GLP-1 RA (15%). Conclusion Although SGLT-2i, DPP-4i, and GLP-1 RAs are recommended as 2nd or 3rd line therapy for type 2 diabetes, important differences exist in the characteristics of users of these drugs. Contrary to existing guidelines, new users of DPP-4i had a higher prevalence of cardiovascular disease at baseline than new users of SGLT2i or GLP-1RA.