Oxidative Stress in Type 2 Diabetes: Impacts from Pathogenesis to Lifestyle Modifications.

Oxidative stress is a critical factor in the pathogenesis and progression of diabetes and its associated complications. The imbalance between reactive oxygen species (ROS) production and the body's antioxidant defence mechanisms leads to cellular damage and dysfunction. In diabetes, chronic hyperglycaemia and mitochondrial dysfunction contribute to increased ROS production, further exacerbating oxidative stress. This oxidative burden adversely affects various aspects of diabetes, including impaired beta-cell function and insulin resistance, leading to disrupted glucose regulation. Additionally, oxidative stress-induced damage to blood vessels and impaired endothelial function contribute to the development of diabetic vascular complications such as retinopathy, nephropathy, and cardiovascular diseases. Moreover, organs and tissues throughout the body, including the kidneys, nerves, and eyes, are vulnerable to oxidative stress, resulting in diabetic nephropathy, neuropathy, and retinopathy. Strategies to mitigate oxidative stress in diabetes include antioxidant therapy, lifestyle modifications, and effective management of hyperglycaemia. However, further research is necessary to comprehensively understand the underlying mechanisms of oxidative stress in diabetes and to evaluate the efficacy of antioxidant interventions in preventing and treating diabetic complications. By addressing oxidative stress, it might be possible to alleviate the burden of diabetes and improve patient outcomes.

Peripheral Neuropathy in Diabetes Mellitus: Pathogenetic Mechanisms and Diagnostic Options.

Diabetic neuropathy (DN) is one of the main microvascular complications of both type 1 and type 2 diabetes mellitus. Sometimes, this could already be present at the time of diagnosis for type 2 diabetes mellitus (T2DM), while it appears in subjects with type 1 diabetes mellitus (T1DM) almost 10 years after the onset of the disease. The impairment can involve both somatic fibers of the peripheral nervous system, with sensory-motor manifestations, as well as the autonomic system, with neurovegetative multiorgan manifestations through an impairment of sympathetic/parasympathetic conduction. It seems that, both indirectly and directly, the hyperglycemic state and oxygen delivery reduction through the vasa nervorum can determine inflammatory damage, which in turn is responsible for the alteration of the activity of the nerves. The symptoms and signs are therefore various, although symmetrical painful somatic neuropathy at the level of the lower limbs seems the most frequent manifestation. The pathophysiological aspects underlying the onset and progression of DN are not entirely clear. The purpose of this review is to shed light on the most recent discoveries in the pathophysiological and diagnostic fields concerning this complex and frequent complication of diabetes mellitus.

The number of risk factors not at target is associated with cardiovascular risk in a type 2 diabetic population with albuminuria in primary cardiovascular prevention. Post-hoc analysis of the NID-2 trial.

BACKGROUND: Nephropathy in Diabetes type 2 (NID-2) study is an open-label cluster randomized clinical trial that demonstrated that multifactorial intensive treatment reduces Major Adverse Cardiac Events (MACEs) and overall mortality versus standard of care in type 2 diabetic subjects with albuminuria and no history of cardiovascular disease. Aim of the present post-hoc analysis of NID- 2 study is to evaluate whether the number of risk factors on target associates with patient outcomes. METHODS: Intervention phase lasted four years and subsequent follow up for survival lasted 10 years. To the aim of this post-hoc analysis, the whole population has been divided into 3 risk groups: 0-1 risk factor (absent/low); 2-3 risk factors (intermediate); 4 risk factors (high). Primary endpoint was a composite of fatal and non-fatal MACEs, the secondary endpoint was all-cause death at the end of the follow-up phase. RESULTS: Absent/low risk group included 166 patients (52.4%), intermediate risk group 128 (40.4%) and high-risk group 23 (7.3%). Cox model showed a significant higher risk of MACE and death in the high-risk group after adjustment for confounding variables, including treatment arm (HR 1.91, 95% CI 1.04-3.52, P = 0.038 and 1.96, 95%CI 1.02-3.8, P = 0,045, respectively, vs absent/low risk group). CONCLUSIONS: This post-hoc analysis of the NID-2 trial indicates that the increase in the number of risk factors at target correlates with better cardiovascular-free survival in patients with type 2 diabetes at high CV risk. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00535925. https://clinicaltrials.gov/ct2/show/NCT00535925.

Cardiac Hypertrophy: From Pathophysiological Mechanisms to Heart Failure Development.

Cardiac hypertrophy develops in response to increased workload to reduce ventricular wall stress and maintain function and efficiency. Pathological hypertrophy can be adaptive at the beginning. However, if the stimulus persists, it may progress to ventricular chamber dilatation, contractile dysfunction, and heart failure, resulting in poorer outcome and increased social burden. The main pathophysiological mechanisms of pathological hypertrophy are cell death, fibrosis, mitochondrial dysfunction, dysregulation of Ca 2 + -handling proteins, metabolic changes, fetal gene expression reactivation, impaired protein and mitochondrial quality control, altered sarcomere structure, and inadequate angiogenesis. Diabetic cardiomyopathy is a condition in which cardiac pathological hypertrophy mainly develop due to insulin resistance and subsequent hyperglycaemia, associated with altered fatty acid metabolism, altered calcium homeostasis and inflammation. In this review, we summarize the underlying molecular mechanisms of pathological hypertrophy development and progression, which can be applied in the development of future novel therapeutic strategies in both reversal and prevention.

An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors block glucose reabsorption in the renal proximal tubule, an insulin-independent mechanism that plays a critical role in glycemic regulation in diabetes. In addition to their glucose-lowering effects, SGLT2 inhibitors prevent both renal damage and the onset of chronic kidney disease and cardiovascular events, in particular heart failure with both reduced and preserved ejection fraction. These unexpected benefits prompted changes in treatment guidelines and scientific interest in the underlying mechanisms. Aside from the target effects of SGLT2 inhibition, a wide spectrum of beneficial actions is described for the kidney and the heart, even though the cardiac tissue does not express SGLT2 channels. Correction of cardiorenal risk factors, metabolic adjustments ameliorating myocardial substrate utilization, and optimization of ventricular loading conditions through effects on diuresis, natriuresis, and vascular function appear to be the main underlying mechanisms for the observed cardiorenal protection. Additional clinical advantages associated with using SGLT2 inhibitors are antifibrotic effects due to correction of inflammation and oxidative stress, modulation of mitochondrial function, and autophagy. Much research is required to understand the numerous and complex pathways involved in SGLT2 inhibition. This review summarizes the current known mechanisms of SGLT2-mediated cardiorenal protection.

Current Knowledge on the Pathophysiology of Lean/Normal-Weight Type 2 Diabetes.

Since early times, being overweight and obesity have been associated with impaired glucose metabolism and type 2 diabetes (T2D). Similarly, a less frequent adult-onset diabetes in low body mass index (BMI) people has been known for many decades. This form is mainly found in developing countries, whereby the largest increase in diabetes incidence is expected in coming years. The number of non-obese patients with T2D is also on the rise among non-white ethnic minorities living in high-income Western countries due to growing migratory flows. A great deal of energy has been spent on understanding the mechanisms that bind obesity to T2D. Conversely, the pathophysiologic features and factors driving the risk of T2D development in non-obese people are still much debated. To reduce the global burden of diabetes, we need to understand why not all obese people develop T2D and not all those with T2D are obese. Moreover, through both an effective prevention and the implementation of an individualized clinical management in all people with diabetes, it is hoped that this will help to reduce this global burden. The purpose of this review is to take stock of current knowledge about the pathophysiology of diabetes not associated to obesity and to highlight which aspects are worthy of future studies.

Efficacy and durability of multifactorial intervention on mortality and MACEs: a randomized clinical trial in type-2 diabetic kidney disease.

BACKGROUND: Multiple modifiable risk factors for late complications in patients with diabetic kidney disease (DKD), including hyperglycemia, hypertension and dyslipidemia, increase the risk of a poor outcome. DKD is associated with a very high cardiovascular risk, which requires simultaneous treatment of these risk factors by implementing an intensified multifactorial treatment approach. However, the efficacy of a multifactorial intervention on major fatal/non-fatal cardiovascular events (MACEs) in DKD patients has been poorly investigated. METHODS: Nephropathy in Diabetes type 2 (NID-2) study is a multicentre, cluster-randomized, open-label clinical trial enrolling 395 DKD patients with albuminuria, diabetic retinopathy (DR) and negative history of CV events in 14 Italian diabetology clinics. Centres were randomly assigned to either Standard-of-Care (SoC) (n = 188) or multifactorial intensive therapy (MT, n = 207) of main cardiovascular risk factors (blood pressure < 130/80 mmHg, glycated haemoglobin < 7%, LDL, HDL and total cholesterol < 100 mg/dL, > 40/50 mg/dL for men/women and < 175 mg/dL, respectively). Primary endpoint was MACEs occurrence by end of follow-up phase. Secondary endpoints included single components of primary endpoint and all-cause death. RESULTS: At the end of intervention period (median 3.84 and 3.40 years in MT and SoC group, respectively), targets achievement was significantly higher in MT. During 13.0 years (IQR 12.4-13.3) of follow-up, 262 MACEs were recorded (116 in MT vs. 146 in SoC). The adjusted Cox shared-frailty model demonstrated 53% lower risk of MACEs in MT arm (adjusted HR 0.47, 95%CI 0.30-0.74, P = 0.001). Similarly, all-cause death risk was 47% lower (adjusted HR 0.53, 95%CI 0.29-0.93, P = 0.027). CONCLUSION: MT induces a remarkable benefit on the risk of MACEs and mortality in high-risk DKD patients. Clinical Trial Registration ClinicalTrials.gov number, NCT00535925. https://clinicaltrials.gov/ct2/show/NCT00535925.

Pathophysiological mechanisms and clinical evidence of relationship between Nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease.

Evidence suggests a close connection between Nonalcoholic Fatty Liver Disease (NAFLD) and increased cardiovascular (CV) risk. Several cross-sectional studies report that NAFLD is related to preclinical atherosclerotic damage, and to coronary, cerebral and peripheral vascular events. Similar results have been showed by prospective studies and also by meta-analyzes on observational studies. The pathophysiological mechanisms of NAFLD are related to insulin resistance, which causes a dysfunction in adipokine production, especially adiponectin, from adipose tissue. A proinflammatory state and an increase in oxidative stress, due to increased reacting oxygen species (ROS) formation with consequent oxidation of free fatty acids and increased de novo lipogenesis with accumulation of triglycerides, are observed. These mechanisms may have an impact on atherosclerotic plaque formation and progression, and they can lead to increased cardiovascular risk in subjects with NAFLD. This review extensively discusses and comments current and developing NAFLD therapies and their possible impact on cardiovascular outcome.

Impact of direct acting antivirals (DAAs) on cardiovascular events in HCV cohort with pre-diabetes.

BACKGROUND AND AIMS: Beyond type 2 diabetes, even a condition of prediabetes is associated with an increased cardiovascular (CV) risk, and HCV infection coexistence represents an exacerbating factor. CV prognosis improvement in prediabetes represents a challenge, due to the increasing prevalence of this metabolic condition worldwide. Hence, we aimed to prospectively assess how direct acting antivirals (DAAs) could affect major cardiovascular events (MACE) in a prediabetic HCV positive cohort. METHODS AND RESULTS: In this prospective multicenter study, we enrolled HCV patients with overt prediabetes. We compared a subgroup of patients treated with DAAs with untreated prediabetic controls. We recorded all CV events occurred during an overall median follow-up of 24 months (IQR 19-34). 770 HCV positive prediabetic patients were enrolled, 398 untreated controls and 372 DAAs treated patients. Overall, the CV events annual incidence was much higher among prediabetic treated patients (1.77 vs. 0.62, p < 0.001), and HCV clearance demonstrated to significantly reduce CV events (RR: 0.411, 95%CI 0.148-1.143; p < 0.001), with an estimated NNT for one additional patient to benefit of 52.1. Moreover, an independent association between a lower rate of CV events and HCV clearance after DAAs was observed (OR 4.67; 95%CI 0.44-53.95; p = 0.016). CONCLUSIONS: HCV eradication by DAAs allows a significant reduction of MACEs in the prediabetic population, and therefore represents a primary objective, regardless of the severity of liver disease and CV risk factors.

Impact of SGLT2 Inhibitors on Heart Failure: From Pathophysiology to Clinical Effects.

Heart failure (HF) affects up to over 20% of patients with type 2 diabetes (T2DM), even more in the elderly. Although, in T2DM, both hyperglycemia and the proinflammatory status induced by insulin resistance are crucial in cardiac function impairment, SGLT2i cardioprotective mechanisms against HF are several. In particular, these beneficial effects seem attributable to the significant reduction of intracellular sodium levels, well-known to exert a cardioprotective role in the prevention of oxidative stress and consequent cardiomyocyte death. From a molecular perspective, patients' exposure to gliflozins' treatment mimics nutrient and oxygen deprivation, with consequent autophagy stimulation. This allows to maintain the cellular homeostasis through different degradative pathways. Thus, since their introduction in the clinical practice, the hypotheses on SGLT2i mechanisms of action have changed: from simple glycosuric drugs, with consequent glucose lowering, erythropoiesis enhancing and ketogenesis stimulating, to intracellular sodium-lowering molecules. This provides their consequent cardioprotective effect, which justifies its significant reduction in CV events, especially in populations at higher risk. Finally, the updated clinical evidence of SGLT2i benefits on HF was summarized. Thus, this review aimed to analyze the cardioprotective mechanisms of sodium glucose transporter 2 inhibitors (SGLT2i) in patients with HF, as well as their clinical impact on cardiovascular events.

Aspirin in a diabetic retinopathy setting: Insights from NO BLIND study.

BACKGROUND AND AIMS: Diabetic retinopathy (DR) is the most common microvascular complication of diabetes. Diabetic macroangiopathies, particularly cardiovascular (CV) diseases, seem closely related to diabetes microvascular complications. Aspirin represents the most prescribed compound in CV prevention. Aspirin impact on DR is still object of debate. As it is already recommended among diabetics at high CV risk, aim of this study was to assess a potential relationship between DR and aspirin therapy, in a type 2 diabetes cohort of patients screened through telemedicine. METHODS AND RESULTS: NO Blind is a cross-sectional, multicenter, observational study, which involved nine Italian outpatient clinics. Primary endpoint was the assessment of the relationship between aspirin treatment and DR. 2068 patients were enrolled in the study, subsequently split in two subpopulations according to either the presence or absence of DR. Overall, 995 subjects were under aspirin therapy. After adjusting for most common potential confounders, age and gender, aspirin reveals significantly associated with DR (OR: 1.72, 95%CI: 1.58-2.89, p = 0.002) and proliferative DR (PDR) (OR: 1.89, 95%CI: 1.24-2.84, p = 0.003). Association comes lost further adjusting for MACEs (OR: 1.28, 95%CI: 0.85-1.42, p = 0.157) (Model 4) and eGFR (OR: 0.93; 95%CI: 0.71-1.22; p = 0.591) (Model 5). CONCLUSION: In this multicenter cross-sectional study including a large sample of outpatients with T2DM, we showed that aspirin was not associated with DR after adjustment for several cardio-metabolic confounders. However, as partially confirmed by our findings, and related to the well-known pro-hemorrhagic effect of aspirin, its use should be individually tailored, even by telemedicine tools.

Adiponectin and insulin resistance are related to restenosis and overall new PCI in subjects with normal glucose tolerance: the prospective AIRE Study.

BACKGROUND: In patients with Normal Glucose Tolerance (NGT) some causes of ischemic heart disease (IHD) were not completely investigated. The role both of metabolic milieu and adipokines in IHD progression was not fully investigated. Our aim was to assess the link between adipokines plasma levels, insulin resistance (IR) and IHD in NGT patients undergoing Percutaneous Coronary Intervention (PCI). METHODS: AIRE is a single-center prospective longitudinal observational study investigating the IHD outcome of NGT subjects who underwent coronary revascularization by PCI in a third level cardiology center at A.O. dei Colli Hospital, University of Campania "Luigi Vanvitelli". Six hundred seventy-nine subjects hospitalized in 2015 for coronary arteriography not suffering from Acute Coronary Syndrome (ACS) in the previous 4 weeks, as well as from all conditions could affect glycemic plasma levels and IR status, were assessed for eligibility. Fifty-four patients with neither history of diabetes nor Altered Fasting Glucose (AFG)/Impaired Fasting Glucose (IGT) after Oral Glucose Tolerance Test (OGTT) were finally enrolled. Primary endpoint was the assessment of the relationship of adipokines and HOMA-IR with the occurrence of restenosis in NGT subjects. As secondary endpoint we assessed the association of the same adipokines and IR with overall ACS events after PCI in NGT subjects. RESULTS: The 54 NGT patients enrolled were mainly males (85%), with a median age of 60 years [IQR 58-63 years]. Only 4 patients (7.4%) experimented restenosis. Median follow-up was equal to 29.5 months [IQR 14.7-34 months]. Adiponectin levels were independently associated to restenosis (OR 0.206; 95% CI 0.053-0.796; p = 0.000). Instead HOMA-IR and adiponectin appeared independently associated both to de novo IHD (OR 9.6*1013; 95% CI 3.026-3.08*1027; p = 0.042 and OR 0.206; 95% CI 0.053-0.796; p = 0.000, respectively) and overall new PCI (OR 1.5*1011; 95% CI 2.593-8.68*1021; p = 0.042 and OR 0.206; 95% CI 0.053-0.796; p = 0.000, respectively). Moreover, we fixed a potential cut-off for adiponectin for risk of restenosis (≤ 8.5 µg/mL) and overall new PCI (≤ 9.5 µg/mL). CONCLUSION: IR and cytokines play a role in progression of any stage of IHD also in NGT subjects. Our results in this setting of patients, though the relatively small sample size, represent a novelty. Future studies on larger populations are needed to analyze more in depth adipokines and insulin resistance role on IHD progression in non-diabetic people.

Moderate-intensity statin therapy seems ineffective in primary cardiovascular prevention in patients with type 2 diabetes complicated by nephropathy. A multicenter prospective 8 years follow up study.

BACKGROUND: Although numerous studies and metanalysis have shown the beneficial effect of statin therapy in CVD secondary prevention, there is still controversy such the use of statins for primary CVD prevention in patients with DM. The purpose of this study was to evaluate the occurrence of total major adverse cardio-vascular events (MACE) in a cohort of patients with type 2 diabetes complicated by nephropathy treated with statins, in order to verify real life effect of statin on CVD primary prevention. METHODS: We conducted an observational prospective multicenter study on 564 patients with type 2 diabetic nephropathy free of cardiovascular disease attending 21 national outpatient diabetes clinics and followed them up for 8 years. 169 of them were treated with statins (group A) while 395 were not on statins (group B). RESULTS: Notably, none of the patients was treated with a high-intensity statin therapy according to last ADA position statement. Total MACE occurred in 32 patients from group A and in 68 patients from group B. Fatal MACE occurred in 13 patients from group A and in 30 from group B; nonfatal MACE occurred in 19 patients from group A and in 38 patients from group B. The analysis of the Kaplan-Meier survival curves showed a not statistically significant difference in the incidence of total (p 0.758), fatal (p 0.474) and nonfatal (p 0.812) MACE between the two groups. HbA1c only showed a significant difference in the incidence of MACE between the two groups (HR 1.201, CI 1.041-1.387, p 0.012). CONCLUSIONS: These findings suggest that, in a real clinical setting, moderate-intensity statin treatment is ineffective in cardiovascular primary prevention for patients with diabetic nephropathy. Trial registration ClinicalTrials.gov Identifier NCT00535925. Date of registration: September 24, 2007, retrospectively registered.

Predictive Value of Fatty Liver Index for Long-Term Cardiovascular Events in Patients Receiving Liver Transplantation: The COLT Study.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is the leading cause of early mortality in orthotopic liver transplantation (OLT) patients. The fatty liver index (FLI) is strongly associated with carotid and coronary atherosclerosis, as well as cardiovascular mortality, surpassing traditional risk factors. Given the lack of data on FLI as a predictor of cardiovascular events in OLT recipients, we conducted a retrospective study to examine this topic. METHODS AND RESULTS: We performed a multicenter retrospective analysis of adult OLT recipients who had regular follow-up visits every three to six months (or more frequently if necessary) from January 1995 to December 2020. The minimum follow-up period was two years post-intervention. Anamnestic, clinical, anthropometric and laboratory data were collected, and FLI was calculated for all patients. CLINICAL TRIAL: gov registration ID NCT05895669. A total of 110 eligible patients (median age 57 years [IQR: 50-62], 72.7% male) were followed for a median duration of 92.3 months (IQR: 45.7-172.4) post-liver transplantation. During this period, 16 patients (14.5%) experienced at least one adverse cardiovascular event (including fatal and non-fatal myocardial infarction and stroke). Receiver Operating Characteristic (ROC) analysis identified a cut-off value of 66.0725 for predicting cardiovascular events after OLT, with 86.7% sensitivity and 63.7% specificity (68% vs. 31%; p = 0.001). Kaplan-Meier analysis showed that patients with FLI > 66 had significantly reduced cardiovascular event-free survival than those with FLI ≤ 66 (log-rank: 0.0008). Furthermore, multivariable Cox regression analysis demonstrated that FLI > 66 and pre-OLT smoking were independently associated with increased cardiovascular risk. CONCLUSIONS: Our findings suggest that FLI > 66 and pre-OLT smoking predict cardiovascular risk in adult OLT recipients.

Precision Medicine in Type 2 Diabetes Mellitus: Utility and Limitations.

Type 2 diabetes mellitus (T2DM) is one of the most widespread diseases in Western countries, and its incidence is constantly increasing. Epidemiological studies have shown that in the next 20 years. The number of subjects affected by T2DM will double. In recent years, owing to the development and improvement in methods for studying the genome, several authors have evaluated the association between monogenic or polygenic genetic alterations and the development of metabolic diseases and complications. In addition, sedentary lifestyle and socio-economic and pandemic factors have a great impact on the habits of the population and have significantly contributed to the increase in the incidence of metabolic disorders, obesity, T2DM, metabolic syndrome, and liver steatosis. Moreover, patients with type 2 diabetes appear to respond to antihyperglycemic drugs. Only a minority of patients could be considered true non-responders. Thus, it appears clear that the main aim of precision medicine in T2DM is to identify patients who can benefit most from a specific drug class more than from the others. Precision medicine is a discipline that evaluates the applicability of genetic, lifestyle, and environmental factors to disease development. In particular, it evaluated whether these factors could affect the development of diseases and their complications, response to diet, lifestyle, and use of drugs. Thus, the objective is to find prevention models aimed at reducing the incidence of pathology and mortality and therapeutic personalized approaches, to obtain a greater probability of response and efficacy. This review aims to evaluate the applicability of precision medicine for T2DM, a healthcare burden in many countries.

Effects of a Combination of Empagliflozin Plus Metformin vs. Metformin Monotherapy on NAFLD Progression in Type 2 Diabetes: The IMAGIN Pilot Study.

Non-alcoholic fatty liver disease (NAFLD) comprises a heterogeneous group of metabolic liver diseases and is characterized by the presence of steatosis in at least 5% of hepatocytes. The aim of our study was to assess the effect of the combination therapy of empagliflozin + metformin vs. metformin monotherapy on NAFLD progression in type 2 diabetic (T2DM) patients. Sixty-three metformin-treated T2DM patients who were SGLT2i-naïve and had an ultrasound diagnosis of NAFLD (aged 60.95 ± 11.14 years; males, 57.1%) were included in the present analysis. Thirty-three started the combination therapy. All patients were observed for 6 months and routinely monitored with anthropometry, blood biochemistry, and FibroScan®/CAP. At the 6-month follow-up, the combination therapy group presented a significant reduction in BMI (30.83 ± 3.5 vs. 28.48 ± 3.25), glycated hemoglobin (8.2 (7.4-8.8)) vs. 7.2 (6.8-7.9), ALT (68.5 (41.5-88.0) vs. 45.00 (38.00, 48.00)), CAP parameter (293.5 (270.0-319.25) vs. 267.00 (259.50, 283.75)) and steatosis degree (p = 0.001) in comparison with the control group, whose parameters remained almost stable over time. In patients affected by T2DM, the combination of empagliflozin + metformin vs. metformin monotherapy ameliorated liver steatosis, ALT levels, body weight, and glycated hemoglobin after a 6-month follow-up.

Impact of gliflozins on cardiac remodeling in patients with type 2 diabetes mellitus & reduced ejection fraction heart failure: A pilot prospective study. GLISCAR study.

AIMS: Type 2 diabetes mellitus (T2DM) and heart failure are closely related entities and together determine an increased risk of mortality compared to patients suffering from only one of these diseases. Sodium-glucose co-transporter type 2 inhibitors (SGLT-2i) have shown favorable effects on cardiovascular system, particularly on heart failure. Aim of this study is to verify whether in individuals with T2DM and heart failure with reduced ejection fraction (HFrEF) treated with SGLT-2i, echocardiographic signs of favorable reverse remodeling follow longitudinal observation. METHODS: 31 subjects with T2DM and HFrEF were finally included. All individuals performed clinical visit, medical history, blood sampling and echocardiography at time 0' and at the end of 6 months of follow-up on SGLT-2i treatment. RESULTS: After 6 months follow-up, left ventricular ejection fraction (LVEF), global work index (GWI), global work efficiency (GWE), global longitudinal strain (GLS), left atrial expansion index (LAEI) and total left atrial emptying fraction (TLAEF), tricuspid annular plane systolic excursion (TAPSE), septal thickness (St), pulmonary artery systolic pressures (PASP) and TAPSE/PASP ratio significantly improved. CONCLUSIONS: Despite the lack of a favorable effect on cardiac remodeling, SGLT-2i treatment significantly improved LV systolic and diastolic function, left atrial (LA) reservoir and total emptying function, RV systolic function and pulmonary artery pressure.

Mortality and risk factors of vaccinated and unvaccinated frail patients with COVID-19 treated with anti-SARS-CoV-2 monoclonal antibodies: A real-world study.

OBJECTIVES: There is a scarcity of data on the outcomes and predictors of therapeutic failure of monoclonal antibodies (mAbs) in frail patients with COVID-19. METHODS: Prospective study including consecutive COVID-19 outpatients referred by primary care physicians for mAb treatment. The outcomes evaluated were 60-day mortality, time to SARS-CoV-2 clearance, need for hospitalization, and O2 therapy. RESULTS: Among 1026 COVID-19 patients enrolled, 60.2% received casirivamab/imdevimab and 39.8% sotrivimab. Median age was 63 years, 52.4% were males and median time from positive nasopharyngeal swab to mAbs administration was 3 days (interquartile range, 2-5). 78.1% were vaccinated. Overall, the 60-day mortality was 2.14%. No differences in outcomes were observed between the two mAbs used. No difference was observed in mortality between vaccinated and unvaccinated patients (P = 0.925); although, lower rate of hospitalization (P <0.005), less need for O2 therapy (P <0.0001) and reduced nasopharyngeal swab negativity time (P <0.0001) were observed in vaccinated patients. Early administration of mAbs was associated with lower mortality (P <0.007), whereas corticosteroid use worsened prognosis (P <0.004). The independent predictors associated with higher mortality were older age (P <0.0001), presence of active hematologic malignancies (P <0.0001), renal failure (P <0.041), and need for O2 therapy (P <0.001). CONCLUSION: This study shows similar effectiveness among mAbs used, regardless of vaccination status and identifies patients with COVID-19 in whom mAbs have poor activity.

High cardiovascular risk in patients with Type 2 diabetic nephropathy: the predictive role of albuminuria and glomerular filtration rate. The NID-2 Prospective Cohort Study.

BACKGROUND: In Type 2 diabetic patients, clinical diagnosis of diabetic nephropathy (DN) is generally based on the concomitant presence of abnormal albuminuria and severe retinopathy. In this high-risk population, cardiovascular (CV) outcome has never been evaluated. METHODS: A cohort of 742 Type 2 diabetic patients with DN from 17 national centres was selected by the presence of persistent albuminuria ≥ 30 mg/day and severe diabetic retinopathy and was followed prospectively. Time to CV event (CV death, non-fatal myocardial infarction, non-fatal stroke, revascularization, major amputation) was the primary composite end point and it was analysed by multivariable Cox's proportional hazards model. The interaction between albuminuria and glomerular filtration rate (GFR) was specifically investigated. RESULTS: Median follow-up was 4.6 years. Overall 242 events (26% of which fatal) were observed in 202 patients. The proportion of CV events increased from 19 to 40% as GFR declined from the highest (≥ 90 mL/min/1.73 m(2)) to the lowest (<45 mL/min/1.73 m(2)) category and was equal to 25 and 33% in microalbuminuria and macroalbuminuria, respectively. In multivariable analysis, the interaction between albuminuria and GFR was statistically significant (P = 0.012). Albuminuria, indeed, had a remarkable prognostic effect in subjects with high GFR that virtually disappeared as GFR became <30 mL/min/1.73 m(2). Age, smoking habit, previous occurrence of myocardial infarction or stroke and proliferative retinopathy were all found to have a statistically significant prognostic effect on CV outcome. CONCLUSIONS: A clinically based diagnosis of DN in Type 2 diabetes allows the identification of subjects with high CV risk. Albuminuria has a relevant prognostic effect on CV morbidity and mortality; its effect is especially pronounced when GFR is normal or near normal.