Aldosterone and aldosterone synthase inhibitors in cardiorenal disease.

Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance.

Repressive H3K27me3 drives hyperglycemia-induced oxidative and inflammatory transcriptional programs in human endothelium.

BACKGROUND: Histone modifications play a critical role in chromatin remodelling and regulate gene expression in health and disease. Histone methyltransferases EZH1, EZH2, and demethylases UTX, JMJD3, and UTY catalyse trimethylation of lysine 27 on histone H3 (H3K27me3). This study was designed to investigate whether H3K27me3 triggers hyperglycemia-induced oxidative and inflammatory transcriptional programs in the endothelium. METHODS: We studied human aortic endothelial cells exposed to high glucose (HAEC) or isolated from individuals with diabetes (D-HAEC). RT-qPCR, immunoblotting, chromatin immunoprecipitation (ChIP-qPCR), and confocal microscopy were performed to investigate the role of H3K27me3. We determined superoxide anion (O2-) production by ESR spectroscopy, NF-κB binding activity, and monocyte adhesion. Silencing/overexpression and pharmacological inhibition of chromatin modifying enzymes were used to modulate H3K27me3 levels. Furthermore, isometric tension studies and immunohistochemistry were performed in aorta from wild-type and db/db mice. RESULTS: Incubation of HAEC to high glucose showed that upregulation of EZH2 coupled to reduced demethylase UTX and JMJD3 was responsible for the increased H3K27me3. ChIP-qPCR revealed that repressive H3K27me3 binding to superoxide dismutase and transcription factor JunD promoters is involved in glucose-induced O2- generation. Indeed, loss of JunD transcriptional inhibition favours NOX4 expression. Furthermore, H3K27me3-driven oxidative stress increased NF-κB p65 activity and downstream inflammatory genes. Interestingly, EZH2 inhibitor GSK126 rescued these endothelial derangements by reducing H3K27me3. We also found that H3K27me3 epigenetic signature alters transcriptional programs in D-HAEC and aortas from db/db mice. CONCLUSIONS: EZH2-mediated H3K27me3 represents a key epigenetic driver of hyperglycemia-induced endothelial dysfunction. Targeting EZH2 may attenuate oxidative stress and inflammation and, hence, prevent vascular disease in diabetes.

Cardio-renal-metabolic disease in primary care setting.

In the primary care setting providers have more tools available than ever before to impact positively obesity, diabetes, and their complications, such as renal and cardiac diseases. It is important to recognise what is available for treatment taking into account diabetes heterogeneity. For those who develop type 2 diabetes (T2DM), effective treatments are available that for the first time have shown a benefit in reducing mortality and macrovascular complications, in addition to the well-established benefits of glucose control in reducing microvascular complications. Some of the newer medications for treating hyperglycaemia have also a positive impact in reducing heart failure (HF). Technological advances have also contributed to improving the quality of care in patients with diabetes. The use of technology, such as continuous glucose monitoring systems (CGM), has improved significantly glucose and glycated haemoglobin A1c (HbA1c) values, while limiting the frequency of hypoglycaemia. Other technological support derives from the use of predictive algorithms that need to be refined to help predict those subjects who are at great risk of developing the disease and/or its complications, or who may require care by other specialists. In this review we also provide recommendations for the optimal use of the new medications; sodium-glucose co-transporter-2 inhibitors (SGLT2i) and Glucagon-like peptide-receptor agonists 1 (GLP1RA) in the primary care setting considering the relevance of these drugs for the management of T2DM also in its early stage.

Concurrent endometrial cancer in atypical endometrial hyperplasia and the role of sentinel lymph nodes: clinical insights from a multicenter experience.

OBJECTIVE: This study aimed to evaluate the prevalence of concurrent endometrial cancer in patients pre-operatively diagnosed with atypical endometrial hyperplasia undergoing hysterectomy. Additionally, we assessed the occurrence of high to intermediate-risk and high-risk tumors according to the ESGO-ESTRO-ESP classification. The study also compared surgical outcomes and complications between patients undergoing simple hysterectomy and those undergoing hysterectomy with sentinel lymph node biopsy. METHODS: In this multicenter retrospective study, patients with a pre-operative diagnosis of atypical endometrial hyperplasia were identified and divided into two groups: Group 1, which included patients treated with total hysterectomy with or without bilateral salpingo-oophorectomy, and Group 2, where sentinel lymph node biopsy was incorporated into the standard surgical treatment. RESULTS: Among 460 patients with atypical endometrial hyperplasia, 192 received standard surgical management (Group 1) and 268 underwent sentinel lymph node biopsy (Group 2). A total of 47.2% (95% CI 42.6% to 51.7%) of patients were upgraded to endometrial cancer on final histopathological examination. High to intermediate-risk and high-risk tumors constituted 12.3% and 9.2% in Group 2 and 7.4% and 3.7% in Group 1. Lymph node metastases were identified in 7.6% of patients with concurrent endometrial cancer who underwent nodal assessment with at least unilateral mapping. Of the 12 sentinel lymph node metastases, 75.0% were micrometastases, 16.7% macrometastases, and 8.3% isolated tumor cells. No significant differences were found in estimated blood loss, operative time, and intra-operative and post-operative complications between the two groups. The rate of patients undergoing sentinel lymph node biopsy doubled every 2 years (OR 2.010, p<0.001), reaching 79.1% in the last 2 years. CONCLUSION: This study found a prevalence of concurrent endometrial cancer of 47.2%, and sentinel lymph node biopsy provided prognostic and therapeutic information in 60.8% of cases. It also allowed for the adjustment of adjuvant therapy in 12.3% of high to intermediate-risk patients without increasing operative time or complication rates.

Optimizing patient selection for secondary cytoreductive surgery in recurrent endometrial cancer.

OBJECTIVE: This retrospective, multicenter, observational study aimed to refine patient selection criteria for secondary cytoreductive surgery in recurrent endometrial cancer. The objective was to identify preoperative predictors of complete cytoreduction, assess surgical complexity, and propose a preoperative predictive scoring system to identify suitable candidates for secondary cytoreductive surgery. METHODS: Data from 331 women with recurrent endometrial cancer were analyzed across three Italian centers from January 2010 to December 2021. Patients were categorized based on treatment received (medical treatment, diagnostic laparoscopy/examination under anesthesia, or secondary cytoreductive surgery). Preoperative predictors, surgical complexity, complications, and a predictive scoring system were assessed. Logistic regression and receiver operating characteristic analysis were used for statistical evaluation. RESULTS: Of the cohort, 56.2% underwent debulking surgery, 17.2% had diagnostic laparoscopy, and 26.6% received medical treatment. Patients undergoing secondary cytoreductive surgery were younger, with a lower body mass index, better performance status, and fewer comorbidities. Single site locoregional relapse was common in secondary cytoreductive surgery patients. Age <65 years, single site relapse, lymph node, and hematogenous relapse were independent predictors of complete cytoreduction. A predictive scoring system demonstrated a clear relationship between the score and the likelihood of complete cytoreduction. CONCLUSION: This study identified age <65 years, single site recurrence, as well as nodal and hematogenous recurrence, as predictive factors for achieving optimal cytoreduction. A predictive scoring system incorporating these factors has been proposed to identify optimal candidates for secondary cytoreductive surgery in recurrent endometrial cancer. The scoring system showed promising predictive accuracy and could aid in refining the decision making process, ensuring appropriate patient selection for secondary cytoreductive surgery. Further prospective studies are warranted to validate and enhance the predictive model.

Mechanisms of benefits of sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction.

For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to reduce the composite of heart failure hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials. While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents. The SGLT2 inhibitors have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and autophagic flux in addition to altering iron homeostasis, which may contribute to improved cardiac energetics and function. These agents also reduce epicardial adipose tissue and alter adipokine signalling, which may play a role in the reductions in inflammation and oxidative stress observed with SGLT2 inhibition. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized. Finally, SGLT2 inhibitors have been shown to reduce myofilament stiffness as well as extracellular matrix remodelling/fibrosis in the heart, improving diastolic function. The SGLT2 inhibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will likely become foundational in the therapy of HFpEF.

Cardiometabolic risk management: insights from a European Society of Cardiology Cardiovascular Round Table.

Metabolic comorbidities are common in patients with cardiorenal disease; they can cause atherosclerotic cardiovascular disease (ASCVD), speed progression, and adversely affect prognosis. Common comorbidities are Type 2 diabetes mellitus (T2DM), obesity/overweight, chronic kidney disease (CKD), and chronic liver disease. The cardiovascular system, kidneys, and liver are linked to many of the same risk factors (e.g. dyslipidaemia, hypertension, tobacco use, diabetes, and central/truncal obesity), and shared metabolic and functional abnormalities lead to damage throughout these organs via overlapping pathophysiological pathways. The COVID-19 pandemic has further complicated the management of cardiometabolic diseases. Obesity, T2DM, CKD, and liver disease are associated with increased risk of poor outcomes of COVID-19 infection, and conversely, COVID-19 can lead to worsening of pre-existing ASCVD. The high rates of these comorbidities highlight the need to improve recognition and treatment of ASCVD in patients with obesity, insulin resistance or T2DM, chronic liver diseases, and CKD and equally, to improve recognition and treatment of these diseases in patients with ASCVD. Strategies to prevent and manage cardiometabolic diseases include lifestyle modification, pharmacotherapy, and surgery. There is a need for more programmes at the societal level to encourage a healthy diet and physical activity. Many pharmacotherapies offer mechanism-based approaches that can target multiple pathophysiological pathways across diseases. These include sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, selective mineralocorticoid receptor antagonists, and combined glucose-dependent insulinotropic peptide/glucagon-like peptide-1 receptor agonist. Non-surgical and surgical weight loss strategies can improve cardiometabolic disorders in individuals living with obesity. New biomarkers under investigation may help in the early identification of individuals at risk and reveal new treatment targets.

Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes.

BACKGROUND: The cardiovascular effects of ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, have not been established. METHODS: In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. RESULTS: A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P = 0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo. CONCLUSIONS: Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck Sharp & Dohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.).

Data from network meta-analyses can inform clinical practice guidelines and decision-making in diabetes management: perspectives of the taskforce of the guideline workshop.

In recent years, several novel agents have become available to treat individuals with type 2 diabetes (T2D), such as sodium-glucose cotransporter-2 inhibitors (SGLT-2i), tirzepatide, which is a dual glucose-dependent insulinotropic polypeptide receptor agonist (GIP RA)/glucagon-like peptide-1 receptor agonist (GLP-1 RA), and finerenone, a non-steroidal mineralocorticoid receptor antagonist (MRA) that confers significant renal and cardiovascular benefits in individuals with (CKD). New medications have the potential to improve the lives of individuals with diabetes. However, clinicians are challenged to understand the benefits and potential risks associated with these new and emerging treatment options. In this article, we discuss how use of network meta-analyses (NMA) can fill this need.

Cardiorenal outcomes by indices of liver steatosis and fibrosis in individuals with type 2 diabetes and atherosclerotic cardiovascular disease: Analyses from VERTIS CV, a randomized trial of the sodium-glucose cotransporter-2 inhibitor ertugliflozin.

AIM: To conduct a post hoc analysis to explore indices of hepatic steatosis/fibrosis and cardiorenal outcomes in the VERTIS CV study. MATERIALS AND METHODS: Patients with type 2 diabetes and atherosclerotic cardiovascular (CV) disease were randomized to ertugliflozin or placebo. Liver steatosis and fibrosis were assessed post hoc using the hepatic steatosis index (HSI) and fibrosis-4 (FIB-4) index to explore associations with cardiorenal outcomes (ertugliflozin and placebo data pooled, intention-to-treat analysis set). Cardiorenal outcomes (major adverse CV events [MACE]; hospitalization for heart failure [HHF]/CV death; CV death; HHF; and a composite kidney outcome) were stratified by baseline HSI and FIB-4 quartiles (Q1-Q4). Change in liver indices and enzymes over time were assessed (for ertugliflozin vs. placebo). RESULTS: Amongst 8246 participants, the mean age was 64.4 years, body mass index 32.0 kg/m2 , HSI 44.0 and FIB-4 score 1.34. The hazard ratios (HRs) for MACE, HHF/CV death, CV death, and HHF by FIB-4 score quartile (Q4 vs. Q1) were 1.48 (95% confidence interval [CI] 1.25, 1.76), 2.0 (95% CI 1.63, 2.51), 1.85 (95% CI 1.45, 2.36), and 2.94 (95% CI 1.98, 4.37), respectively (P < 0.0001 for all). With HSI, the incidence of HHF was higher in Q4 versus Q1 (HR 1.52 [95% CI 1.07, 2.17]; P < 0.05). The kidney composite outcome did not differ across FIB-4 or HSI quartiles. Liver enzymes and HSI decreased over time with ertugliflozin. CONCLUSION: In VERTIS CV, higher FIB-4 score was associated with CV events. HSI correlated with HHF. Neither measure was associated with the composite kidney outcome. Ertugliflozin was associated with a reduction in liver enzymes and HSI.

Major determinants of survival in recurrent endometrial cancer-the role of secondary cytoreductive surgery: a multicenter study.

OBJECTIVE: The main objective of the study was to assess the influence of different clinical and therapeutic variables on the oncological outcomes of patients with endometrial cancer relapse. In particular, we evaluated the impact of cytoreductive surgery with the achievement of complete gross resection. METHODS: This is a multicenter retrospective cohort study conducted in three centers in Italy and including all patients with first relapse of endometrial cancer from January 2010 to December 2021. RESULTS: Data from 331 women with recurrent endometrial cancer were analyzed. Secondary cytoreductive surgery was performed in 56.2% of cases (186 patients). Complete gross resection was achieved in 178 patients (95.7%). Complete gross resection conferred a statistically significant survival benefit both for post-relapse survival and post-relapse free survival (3 years post-relapse survival: 75.4% vs 56.4%, p<0.001; 3 years post-relapse free survival: 32.6% vs 26.5%, p=0.027). At multivariate Cox regression analysis, age ≥75 years, Eastern Cooperative Oncology Group Performance Status ≥2, the advanced-metastatic risk group, complete gross resection, and multiple site relapses were identified as independent significant predictors for post-relapse survival; regarding post-relapse free survival, only age ≥75, the high and advanced-metastatic risk groups, and complete gross resection confirmed their statistical significance. CONCLUSIONS: Secondary cytoreductive surgery with achievement of complete gross resection was confirmed to be an independent positive predictor for survival in patients with recurrent endometrial cancer and should be considered a valid primary treatment in the therapeutic decision-making process.

Long-term survival outcomes in high-risk endometrial cancer patients undergoing sentinel lymph node biopsy alone versus lymphadenectomy.

OBJECTIVE: Endometrial cancer is the most common gynecologic neoplasm. To date, international guidelines recommend sentinel lymph node biopsy for low-risk neoplasms, while systematic lymphadenectomy is still considered for high-risk cases. This study aimed to compare the long-term survival of high-risk patients who were submitted to sentinel lymph node biopsy alone versus systematic pelvic lymphadenectomy. METHODS: Patients with high-risk endometrial cancer according to the 2021 European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology risk classification were retrospectively analyzed. The primary aim of the study was to compare the long-term overall survival and disease-free survival of high-risk endometrial cancer patients undergoing sentinel lymph node biopsy versus systematic lymphadenectomy. A supplementary post-hoc survival analysis of cases with nodal metastasis was performed to compare sentinel lymph node and lymphadenectomy survival outcomes in this subset of patients. RESULTS: The study enrolled 237 patients with histologically proven high-risk endometrial cancer. Patients were followed up for a median of 31 months (IQR 18-40). During the follow-up, 38 (16.0%) patients had a recurrence, and 19 (8.0%) patients died. Disease-free survival (85.2% vs 82.8%; p=0.74) and overall survival (91.3% vs 92.6%; p=0.62) were not different between the sentinel lymph node alone and lymphadenectomy groups. Furthermore, neither overall survival (96.1% vs 91.4%; p=0.43) nor disease-free survival (83.7% vs 76.4%; p=0.46) were different among sentinel lymph node alone and lymphadenectomy groups in patients with nodal metastasis. CONCLUSIONS: Sentinel lymph node mapping alone in high-risk endometrial cancer appears to be an oncologically safe technique over a long observational time. Systematic lymphadenectomy in this population does not offer a survival advantage.

Human papillomavirus independent status on pathologic response and outcomes in locally advanced cervical cancer managed with chemoradiotherapy followed by surgery.

OBJECTIVE: While human papillomavirus (HPV) has been shown to play a significant role in cervical cancer carcinogenesis (HPV associated cases), a considerable percentage of cervical cancers occur independently of HPV status (HPV independent). METHODS: In this retrospective study of 254 locally advanced cervical cancer patients treated with chemoradiotherapy and radical surgery, HPV genotypes were determined using the Anyplex II HPV28 kit that uses multiplex, real time polymerase chain reaction technology. The primary endpoints of this study were to evaluate the complete response to chemoradiotherapy (pathologic complete response), the presence of microscopic (<3 mm, pathologic micro partial response, group 1) and macroscopic (>3 mm, pathologic macro partial response, group 2) residual carcinoma in the cervix, and the persistence of metastatic lymph nodes (group 3) in HPV independent cervical cancers. Secondary endpoints were evaluation of disease-free survival and overall survival. RESULTS: Of 254 patients studied, 21 cases (8.3%) of cervical cancer were determined to be HPV independent. The percentage of pathologic complete response was found to be higher in the HPV associated group compared with the HPV independent group (p<0.001). In the HPV associated cervical cancer group, 5 year disease free survival was found to be 80.8% versus 59.9% in the HPV independent group (p=0.014). Overall survival was also higher in the HPV associated group (87.9%) compared with the HPV independent patients (69.4%) (p=0.023). In the multivariate analysis, the International Federation of Gynecology and Obstetrics (FIGO) stage and HPV genotypes maintained their relevant impact on pathologic complete response to chemoradiotherapy: FIGO stages IIIC1 and IIIC2 were associated with a 13-fold increased risk for the presence of metastatic lymph nodes compared with group 1 (p<0.001). HPV independent cervical cancers showed the highest risk for the development of macroscopic/stable disease (p=0.007), and persistence of metastatic lymph nodes (p=0.004) versus group 1, respectively. CONCLUSIONS: This study showed that HPV status at diagnosis could be a relevant factor for clinical outcomes in locally advanced cervical cancer patients.

The year in cardiovascular medicine 2021: diabetes and metabolic disorders.

In the current paper, we review recently published studies that are helping us to understand how the treatment landscape for glucagon-like peptiide-1 receptor agonists and sodium glucose cotransporter 2 inhibitors is moving forward. We have also included relevant articles related to cardiovascular disease prevention in the setting of obesity, atherogenic dyslipidaemia and chronic kidney disease.

Vascular repair and regeneration in cardiometabolic diseases.

Chronic cardiometabolic assaults during type 2 diabetes (T2D) and obesity induce a progenitor cell imbalance in the circulation characterized by overproduction and release of pro-inflammatory monocytes and granulocytes from the bone marrow alongside aberrant differentiation and mobilization of pro-vascular progenitor cells that generate downstream progeny for the coordination of blood vessel repair. This imbalance can be detected in the peripheral blood of individuals with established T2D and severe obesity using multiparametric flow cytometry analyses to discern pro-inflammatory vs. pro-angiogenic progenitor cell subsets identified by high aldehyde dehydrogenase activity, a conserved progenitor cell protective function, combined with lineage-restricted cell surface marker analyses. Recent evidence suggests that progenitor cell imbalance can be reversed by treatment with pharmacological agents or surgical interventions that reduce hyperglycaemia or excess adiposity. In this state-of-the-art review, we present current strategies to assess the progression of pro-vascular regenerative cell depletion in peripheral blood samples of individuals with T2D and obesity and we summarize novel clinical data that intervention using sodium-glucose co-transporter 2 inhibition or gastric bypass surgery can efficiently restore cell-mediated vascular repair mechanisms associated with profound cardiovascular benefits in recent outcome trials. Collectively, this thesis generates a compelling argument for early intervention using current pharmacological agents to prevent or restore imbalanced circulating progenitor content and maintain vascular regenerative cell trafficking to sites of ischaemic damage. This conceptual advancement may lead to the design of novel therapeutic approaches to prevent or reverse the devastating cardiovascular comorbidities currently associated with T2D and obesity.

Non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.

Despite existing treatments, patients with heart failure and chronic kidney disease (CKD) remain at high risk for adverse outcomes and progression to end-stage disease. Steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone reduce mortality but remain under-prescribed due to the perceived risk of hyperkalaemia and hormonal side effects. The discovery of non-steroidal MRAs represents a major new dimension in cardiorenal disease therapy. Non-steroidal MRAs have high affinity and specificity for the mineralocorticoid receptor (MR) and differ from both steroidal agents and each other with respect to important physiochemical, pharmacodynamic, and pharmacokinetic parameters. Similar to their steroidal counterparts, they have beneficial anti-inflammatory, anti-remodelling, and anti-fibrotic properties in the kidneys, heart, and vasculature. There are several non-steroidal MRAs under development and clinical assessment; of these, only esaxerenone and finerenone are approved for treatment globally. In Japan, esaxerenone is approved for essential hypertension and has been studied in diabetic nephropathy. Compared with steroidal MRAs, finerenone more potently inhibits MR co-regulator recruitment and fibrosis and distributes more evenly between the heart and kidneys. The landmark Phase III trials FIGARO-DKD and FIDELIO-DKD demonstrated that finerenone-reduced major kidney and cardiovascular events on top of maximally tolerated renin-angiotensin-aldosterone system inhibition in patients with CKD associated with Type 2 diabetes. Non-steroidal MRAs are currently under evaluation in heart failure and for synergistic treatment with sodium-glucose contransporter 2 inhibitors. These ground-breaking agents could become an important therapy across the spectrum of cardiorenal disease.

Prevalence of sonographic signs in women with uterine sarcoma: a systematic review and meta-analysis.

OBJECTIVE: To assess the prevalence of sonographic signs in women with uterine sarcoma. MATERIALS AND METHODS: A systematic review and meta-analysis were performed. Five electronic databases were searched from inception to June 2022 for all studies allowing calculation of the prevalence of sonographic signs in women with uterine sarcoma. Pooled prevalence with 95% confidence intervals was calculated for each sonographic sign and was a priori defined as "very high" when it was ≥ 80%, "high" when it ranged from 80% to 70%, and less relevant when it was ≤ 70%. RESULTS: 6 studies with 317 sarcoma patients were included. The pooled prevalence was: · 25.0% (95%CI:15.4-37.9%) for absence of visibility of the myometrium. · 80.5% (95%CI:74.8-85.2%) for solid component. · 78.3% (95%CI:59.3-89.9%) for inhomogeneous echogenicity of solid component. · 47.9% (95%CI:41.1-54.8%) for cystic areas. · 80.7% (95%CI:68.3-89.0%) for irregular walls of cystic areas. · 72.3% (95%CI:16.7-97.2%) for anechoic cystic areas. · 54.8% (95%CI:34.0-74.1%) for absence of shadowing. · 73.5% (95%CI:43.3-90.9%) for absence of calcifications. · 48.7% (95%CI:18.6-79.8%) for color score 3 or 4. · 47.3% (95%CI:37.0-57.8%) for irregular tumor borders. · 45.4% (95%CI:27.6-64.3%) for endometrial cavity not visualizable. · 10.9% (95%CI:3.5-29.1%) for free pelvic fluid. · 6.4% (95%CI:1.1-30.2%) for ascites. · 21.2% (95%CI:2.1-76.8%) for intracavitary process. · 81.5% (95%CI:56.1-93.8%) for singular lesion.. CONCLUSION: Solid component, irregular walls of cystic areas, and singular lesions are signs with very high prevalence, while inhomogeneous echogenicity of solid component, anechoic cystic areas, and absence of calcifications are signs with high prevalence. The remaining signs were less relevant.

Clinical Impact of Pathologic Residual Tumor in Locally Advanced Cervical Cancer Patients Managed by Chemoradiotherapy Followed by Radical Surgery: A Large, Multicenter, Retrospective Study.

BACKGROUND: Exclusive chemoradiation (E-CT/RT) represents the standard of treatment for locally advanced cervical cancer (LACC). Chemoradiation (CT/RT) followed by radical surgery (RS) may play a role for patients with a suboptimal response to CT/RT or in low-income countries with limited access to radiotherapy. Histologic assessment of residual tumor after CT/RT and RS allows accurate definition of prognostic categories. METHODS: Data on patients with FIGO stages 1B2 to 4A cervical cancer managed by CT/RT and RS from June 1996 to March 2020 were retrospectively analyzed. Pathologic response on the cervix was defined as complete (pCR), microscopic (persistent tumor foci ≤ 3 mm) (pmicroR), or macroscopic (persistent tumor foci > 3 mm) (pmacroR). Lymph node (LN) residual tumor was classified as absent or present. RESULTS: The 701 patients in this study underwent CT/RT and RS. Of the 701 patients, 293 (41.8%) had pCR, 188 (26.8%) had pmicroR, and 220 (31.4%) had pMacroR. Residual tumor was found in the pelvic lymph nodes of 66 (9.4%) patients and the aortic lymph nodes of 29 (4.1%) patients. The 5-year DFS and OS were respectively 86.6% and 92.5% in the pCR cases, 80.3% and 89.1% in the pmicroR cases, and 56.2% and 68.8% in the pmacroR cases. Among the patients with lymph node residual tumor, the 5-year DFS and OS were respectively 16.7% and 40% in the pCR cases, 35.4% and 53.3% in the pmicroR cases, and 31.7% and 31.1% in the pmacroR cases. Cervical residual tumor,, positive pelvic LNs, and positive aortic LNs were associated with worse DFS and OS in both the uni- and multivariate analyses. CONCLUSIONS: Persistence of pathologic residual tumor on the cervix and LNs after CT/RT are reliable predictors of survival for LACC patients undergoing CT/RT and adjuvant surgery.

Eligibility for Dapagliflozin and Empagliflozin in a Real-world Heart Failure Population.

BACKGROUND: We investigated eligibility for dapagliflozin and empagliflozin in a real-world heart failure (HF) cohort based on selection criteria of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure), and EMPEROR (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction and Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with APreserved Ejection Fraction) trials. METHODS AND RESULTS: Selection criteria were applied to the Swedish HF registry outpatient population according to 3 scenarios: (i) a "trial scenario" applying all selection criteria; (ii) a "pragmatic scenario" applying the most clinically relevant criteria; and (iii) a "label scenario" following the regulatory agencies labels. Of the 49,317 patients, 55% had an ejection fraction of less than 40% and were assessed for eligibility based on DAPA-HF and EMPEROR-Reduced, 45% had ejection fraction of 40% or greater and were assessed based on EMPEROR-Preserved and DELIVER. Eligibility using trial, pragmatic, and label scenarios was 35%, 61%, and 80% for DAPA-HF; 31%, 55%, and 81% for EMPEROR-Reduced; 30%, 61%, and 74% for DELIVER; and 32%, 59%, and 75% for EMPEROR-Preserved, respectively. The main selection criteria limiting eligibility were HF duration and N-terminal pro-B type natriuretic peptide levels. Eligible patients had more severe HF, more comorbidities, higher use of HF treatments and higher mortality and morbidity.Clinical Highlights: Large clinical trials for the approval of new drugs in heart failure often apply numerous selection criteria, limiting the generalizability of trial findings to real-world populations. We assessed eligibility for dapagliflozin and empagliflozin according to trial criteria, the more practical criteria usually applied in daily practice for treatment selection, and the criteria mandated by regulatory agencies, in a real-word heart failure population. Our results from the Swedish Heart Failure Registry show that a great number of patients with heart failure might be candidates for these therapies, which have been shown to significantly decrease morbidity and mortality; therefore, their use should be implemented in clinical practice. LAY SUMMARY: When strictly applying selection criteria used in clinical trials, only one-third of a real-world heart failure population is eligible for treatment with empagliflozin and dapagliflozin. Adopting approaches that consider the most meaningful criteria, that is, those most clinically relevant or those mandated by regulatory agencies, significantly broadened eligibility. These results might contribute to future trial design taking into consideration the characteristics of real-world populations, feasibility, and potential cost benefits. CONCLUSIONS: In a real-world HF setting, eligibility for sodium glucose co-transporter-2 inhibitors was similar whether selection criteria from DAPA-HF or EMPEROR-Reduced were applied in HFrEF, or EMPEROR-Preserved or DELIVER in HFpEF. These data might help stakeholders assessing the consequences of future trial eligibility.

Initial eGFR Changes with Ertugliflozin and Associations with Clinical Parameters: Analyses from the VERTIS CV Trial.

INTRODUCTION: Using data from the ertugliflozin cardiovascular outcomes trial in patients with type 2 diabetes mellitus (VERTIS CV; NCT01986881), associations between the initial estimated glomerular filtration rate (eGFR) "dip" with eGFR slope, glucosuria/natriuresis-related measures, and safety were investigated. METHODS: Patients were categorized into tertiles based on change in eGFR at week 6: >+1.00 mL/min/1.73 m2 (tertile 1), >-5.99 and ≤+1.00 (tertile 2), and ≤-6.00 (tertile 3). eGFR slope after week 6 and week 18 was assessed by tertile. Glucosuria/natriuresis-related measures were also determined. Adverse events (AEs) were analyzed in the acute (baseline-week 6) and chronic periods (week 6-30 days after last dose of trial medication). RESULTS: In the ertugliflozin group, chronic eGFR slopes (95% CI, mL/min/1.73 m2/year; weeks 6-156) were -0.76 (-1.03, -0.50), -0.29 (-0.51, -0.07), and -0.05 (-0.26, 0.17) in tertiles 1, 2, and 3, respectively (p value <0.001), and approximately -1.5 mL/min/1.73 m2/year across tertiles in the placebo group (p value = 0.79). At week 18, least squares mean (LSM) changes from baseline in glycated hemoglobin (%) were -0.77, -0.71, and -0.67 in tertiles 1, 2, and 3, respectively, in the ertugliflozin group; a similar tertile-associated trend was observed for uric acid. At week 18, LSM changes from baseline in hematocrit (%) were 2.07, 2.33, and 2.55 in tertiles 1, 2, and 3, respectively, in the ertugliflozin group; similar tertile-associated trends were observed for blood pressure. All pinteraction values were <0.0001 for glucosuria- and natriuresis-related measures. Kidney-related AEs were reported more frequently in tertiles 3 and 2 in the chronic period for both placebo- and ertugliflozin-treated groups. In both periods and in all tertiles, incidences of AEs did not differ between placebo- and ertugliflozin-treated groups. CONCLUSION: With ertugliflozin, the tertile with the largest initial dip in eGFR had a slower rate of chronic eGFR decline. Initial eGFR changes were associated with changes in both glucosuria- and natriuresis-related measures.