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Aim: To assess weight loss and cardiorenal outcomes by baseline body mass index (BMI) in VERTIS CV. Methods: Patients with type 2 diabetes and atherosclerotic cardiovascular (CV) disease were randomized to ertugliflozin or placebo. These post hoc analyses evaluated cardiometabolic and cardiorenal outcomes (a composite of death from CV causes or hospitalization for heart failure [HHF], CV death, HHF and an exploratory composite kidney outcome including ≥40% estimated glomerular filtration rate [eGFR] decrease) by baseline BMI, using conventional clinical categories and Cox proportional hazards models. Results: In total, 8246 adults were randomized (mean age 64.4 years, diabetes duration 13.0 years, BMI 32.0 kg/m2, 61% with BMI >30 kg/m2). Absolute body weight reduction was greater with ertugliflozin versus placebo at 3 and 5 years in the overall population (p < 0.001) and across BMI subgroups. Ertugliflozin increased the proportion of participants achieving ≥5% and ≥10% body weight reduction (ertugliflozin 34.9% and 13.6%, placebo 19.4% and 4.1%; odds ratio [95% confident interval, CI], 2.21 [1.76–2.77] and 3.65 [2.39–5.57], respectively) at 5 years. No significant difference was observed in the effect of ertugliflozin on HHF across BMI subgroups (Pinteraction = 0.61). Similarly, no significant difference was observed in the effect of ertugliflozin on the kidney composite outcome across BMI subgroups (Pinteraction = 0.39). Results were similar for other CV outcomes, and safety was consistent with the known ertugliflozin profile. Conclusion: Weight loss was observed across baseline BMI and was sustained over 5 years of follow‐up. The effects of ertugliflozin on HHF and kidney composite were consistent across baseline BMI. [ABSTRACT FROM AUTHOR]

Background and Aims Hyperglycaemia during gestational diabetes (GD) predisposes women and their offspring to later cardiometabolic disease. The hyperglycaemia-mediated epigenetic changes remain to be elucidated. Methyltransferase MLL1-induced trimethylation of histone 3 at lysine 4 (H3K4me3) activates inflammatory and oxidative phenotype. This epigenetic mark in GD women and its transmission to the offspring were investigated. Methods Peripheral blood mononuclear cells (PBMC) were collected from GD and control (C) women and also from adolescents born to women of both groups. Endothelial human umbilical vein endothelial cells (HUVEC) and cord blood mononuclear cells (CBMC) were from umbilical cords. The NF-κBp65 and NOX4 expressions were investigated by reverse transcription quantitative polymerase chain reaction and immunofluorescence (IF). MLL1 and H3K4me3 were investigated by immunoblotting and IF. H3K4me3 on NF-κBp65 and NOX4 promoters was studied by chromatin immunoprecipitation. Superoxide anion generation was measured by electron spin resonance spectroscopy. Plasma cytokines were measured by enzyme-linked immunosorbent assay. To investigate the role of MLL1, HUVEC were exposed to inhibitor MM102 or siRNA transfection. Results PBMC, CBMC, and HUVEC showed an increase of NF-κBp65 , IL-6 , ICAM-1 , MCP-1 , and VCAM-1 mRNAs. These findings were associated with H3K4me3 enrichment in the promoter of NF-κBp65. Elevated H3K4me3 and cytokine levels were observed in GD adolescents. MLL1 drives H3K4me3 not only on NF-kB p65 , but also on NOX4 promoter. Inhibition of MLL1 blunted NF-κBp65 and NOX4 by modulating inflammatory and oxidative phenotype. Conclusions Such proof-of-concept study shows persistence of MLL1-dependent H3K4me3 in offspring born to GD women, suggesting an epigenetic-driven transmission of maternal phenotype. These findings may pave the way for pharmacological reprogramming of adverse histone modifications to mitigate abnormal phenotypes underlying early ASCVD. [ABSTRACT FROM AUTHOR]

With the increasing burden of diabetes as a cause of macro- and microvascular disease linked to the epidemics of obesity, attention is being paid to dysglycaemic states that predict and precede the development of type 2 diabetes. Such conditions, termed pre-diabetes, are characterized by fasting plasma glucose, or plasma glucose levels on an oral glucose tolerance test, or values of glycated haemoglobin intermediate between 'normal' values and those characterizing diabetes. These last are by definition associated, in epidemiological terms, with a higher incidence of microvascular disease—mostly retinopathy. Pre-diabetes overlaps with the components of the 'metabolic syndrome'—among which are excess visceral adiposity; hypertension; hypertriglyceridaemia; high levels of small, dense low-density lipoproteins; and metabolic-associated fatty liver disease. There is little doubt that pre-diabetes has important prognostic implications, especially for the occurrence of myocardial infarction, ischaemic stroke, and peripheral arterial disease. It is disputed, however, whether pre-diabetes is itself an actionable disease entity, in addition to the risk factors characterizing it. Because of this uncertainty, the latest European Society of Cardiology guidelines chose not to include pre-diabetes as a treatment target for atherosclerotic cardiovascular disease, at variance from the three previous editions of such guidelines. This is spurring a debate, the Pro and Contra arguments featured in the present debate article. [ABSTRACT FROM AUTHOR]

Aim: To conduct post hoc analyses of the VERTIS CV (NCT01986881) trial to explore the effects of ertugliflozin on serum uric acid (UA) and gout‐related outcomes. Materials and Methods: Participants with type 2 diabetes and atherosclerotic cardiovascular disease were randomised (1:1:1) to placebo, ertugliflozin 5 mg or ertugliflozin 15 mg. Mean UA over time (260 weeks) was evaluated for pooled ertugliflozin versus placebo overall, and by baseline quintile of UA (≤4.3 mg/dL [≤255.8 µmol/L], >4.3–5.1 mg/dL [>255.8–303.4 µmol/L], >5.1–5.8 mg/dL [>303.4–345.0 µmol/L], >5.8–6.9 mg/dL [>345.0–410.4 µmol/L] and >6.9 mg/dL [>410.4 µmol/L]), glycated haemoglobin level, albuminuria status, estimated glomerular filtration rate and KDIGO (Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease) risk category. The effect of ertugliflozin on a composite of gout onset or initiation of anti‐gout medication was assessed. Results: The mean UA levels at baseline were 5.67 and 5.62 mg/dL in the placebo and ertugliflozin groups, respectively. Ertugliflozin reduced UA over Weeks 6–260 compared with placebo, with least squares mean (LSM) changes (95% confidence interval [CI]) from baseline at Week 260 of 0.07 mg/dL (−0.02, 0.15) and −0.19 mg/dL (−0.25, −0.13) in the placebo and pooled ertugliflozin groups, respectively. At Week 260, placebo‐adjusted LSM change (95% CI) from baseline in UA was −0.26 mg/dL (−0.36, −0.16) with ertugliflozin. Ertugliflozin was associated with reductions in UA across baseline UA quintiles compared with placebo. The incidence of the composite of gout‐related outcomes was 84/2539 (3.3%) for placebo and 133/5091 (2.6%) for ertugliflozin (hazard ratio for the composite 0.76 [95% CI 0.580, 1.002]). Conclusions: Ertugliflozin was generally associated with lowering UA overall and across subgroups compared with placebo, and numerically reduced rates of gout‐related outcome events. [ABSTRACT FROM AUTHOR]

Background: Menopause, a natural phase in a woman's life, often adversely affects physical, mental, sexual, and emotional well-being due to low estrogen levels. This study examines the impact of vaginal ovules with tocopherol acetate (Filme Gyno-V® ovules, manufactured by Panin Srl and distributed by Hulka Srl, Italy), 500 mg per ovule, on vaginal health in pre- and menopausal women. Methods: Fifty women aged 50–70 were divided into menopausal (28) and premenopausal (22) cohorts and treated with the ovules for two weeks, with assessments before and after treatment. Results: The findings showed that distressing symptoms of vaginal atrophy, such as dryness, itching, and pain during intercourse, were resolved post-treatment. A molecular analysis revealed a reduction in Escherichia coli in both cohorts and an increase in three species of Lactobacillus in premenopausal patients. Conclusions: This study concludes that Filme Gyno-V ovules may benefit vaginal health by alleviating atrophy symptoms and promoting healthy vaginal microbiota. [ABSTRACT FROM AUTHOR]

The article discusses a study that examined the relationship between hypoglycemia and kidney events in individuals with type 2 diabetes and cardiovascular disease. The study found no significant association between hypoglycemia events and adverse kidney outcomes. However, it did find that a previous adverse kidney outcome was linked to a higher risk of subsequent hypoglycemia events. The authors recommend further research using real-world data to explore this association and the safety of glucose-lowering medications. [Extracted from the article]

Simple Summary: We systematically reviewed the literature on port site metastases in low- and intermediate-risk endometrial carcinoma. We searched six electronic databases and compared data on PSM from the included studies, finding seven studies and 13 cases of PSM in patients with low- or intermediate-risk endometrial carcinoma. Local resection and radiotherapy appear to be the most appropriate treatment approaches. Unfortunately, no consensus has been reached about treatment, and the prognosis appears poor. Background: Port site metastasis (PSM) has been reported as a rare metastasis in women with endometrial carcinoma (EC). However, even more rarely, it has also been described in patients with low- or intermediate-risk EC. Unfortunately, knowledge appears limited on the topic. Objectives: Our objective was to systematically review the literature on PSM in low- or intermediate-risk EC. Search Strategy: A systematic review of the literature was performed by searching six electronic databases from their inception to January 2023. Selection Criteria: We included in our research all peer-reviewed studies which reported PSM in low- or intermediate-risk EC women. Data Collection and Analysis: Data on PSM were collected from the included studies and compared. Results: Seven studies with 13 patients (including our case) were included in the systematic review. PSM was reported in patients with low- or intermediate-risk EC independently from tumor histologic characteristics, endoscopic approach, lymph node staging type, number and site of the port, route of specimen removal, prevention strategies for PSM, and concomitant metastases. Among several proposed treatments, local resection and radiotherapy with or without chemotherapy might be the most appropriate ones. Nevertheless, the prognosis appears poor. Conclusions: In patients with low- or intermediate-risk EC, PSM can occur as a rare metastasis, regardless of tumor characteristics or surgical strategy. Unfortunately, no consensus has been reached regarding treatment, and the prognosis appears poor. Additional cases are needed in order to confirm and further explore this rare EC metastasis. [ABSTRACT FROM AUTHOR]

This article provides a summary of the top 10 papers in diabetes and metabolic disorders published in 2023, as selected by the editors of the European Heart Journal. The focus is on practical papers that address the identification and management of patients with diabetes and cardiovascular disease. The article highlights the 2023 European Society of Cardiology guidelines for managing cardiovascular disease in patients with diabetes, which emphasize the evaluation and identification of patients with diabetes and chronic kidney disease. The guidelines also introduce a new score, called SCORE2-Diabetes, to estimate the 10-year risk of myocardial infarction and stroke in patients with type 2 diabetes. Other topics covered include the association of loneliness and social isolation with cardiovascular disease in patients with diabetes, the efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with heart failure and peripheral artery disease, the use of glucagon-like peptide-1 receptor agonists in cardiovascular prevention, and the impact of non-statin lipid-lowering agents on the risk of developing new-onset diabetes. Overall, these papers provide valuable insights into the management and prevention of cardiovascular disease in patients with diabetes. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]