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.

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.

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.

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.

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.

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.

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.

Coronary Microvascular Dysfunction in Diabetes Mellitus: Pathogenetic Mechanisms and Potential Therapeutic Options.

Diabetic patients are frequently affected by coronary microvascular dysfunction (CMD), a condition consisting of a combination of altered vasomotion and long-term structural change to coronary arterioles leading to impaired regulation of blood flow in response to changing cardiomyocyte oxygen requirements. The pathogenesis of this microvascular complication is complex and not completely known, involving several alterations among which hyperglycemia and insulin resistance play particularly central roles leading to oxidative stress, inflammatory activation and altered barrier function of endothelium. CMD significantly contributes to cardiac events such as angina or infarction without obstructive coronary artery disease, as well as heart failure, especially the phenotype associated with preserved ejection fraction, which greatly impact cardiovascular (CV) prognosis. To date, no treatments specifically target this vascular damage, but recent experimental studies and some clinical investigations have produced data in favor of potential beneficial effects on coronary micro vessels caused by two classes of glucose-lowering drugs: glucagon-like peptide 1 (GLP-1)-based therapy and inhibitors of sodium-glucose cotransporter-2 (SGLT2). The purpose of this review is to describe pathophysiological mechanisms, clinical manifestations of CMD with particular reference to diabetes, and to summarize the protective effects of antidiabetic drugs on the myocardial microvascular compartment.

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.

The Role of Neuropathy Screening Tools in Patients Affected by Fibromyalgia.

Fibromyalgia syndrome (sFM) is one of the most common causes of chronic pain. This study aimed to assess the presence of small and large fiber impairment in fibromyalgic patients by applying validated scores used in the screening for diabetic neuropathy. The endpoints for the study were the assessment of neuropathy prevalence in sFM patients using the NerveCheck Master (NCM), the Michigan Neuropathy Screening Instrument (MNSI), the Diabetic Neuropathy Symptom (DNS) and the Douleur Neuropathique 4 Questions (DN4). The sample was composed of 46 subjects: subjects with sFM (n = 23) and healthy controls (HC) (n = 23). The positivity rates in each group for DN4 were significantly different (p < 0.001), with a prevalence in symptomatic subjects of 56.3% (n = 9) among sFM individuals. A similar difference was also observed with the DNS total score (p < 0.001). NCM and MNSI did not disclose significant differences between the two groups. This finding seems to confirm the data regarding the prevalence of a neuropathic pain in sFM patients.

Dysregulated Epicardial Adipose Tissue as a Risk Factor and Potential Therapeutic Target of Heart Failure with Preserved Ejection Fraction in Diabetes.

Cardiovascular (CV) disease and heart failure (HF) are the leading cause of mortality in type 2 diabetes (T2DM), a metabolic disease which represents a fast-growing health challenge worldwide. Specifically, T2DM induces a cluster of systemic metabolic and non-metabolic signaling which may promote myocardium derangements such as inflammation, fibrosis, and myocyte stiffness, which represent the hallmarks of heart failure with preserved ejection fraction (HFpEF). On the other hand, several observational studies have reported that patients with T2DM have an abnormally enlarged and biologically transformed epicardial adipose tissue (EAT) compared with non-diabetic controls. This expanded EAT not only causes a mechanical constriction of the diastolic filling but is also a source of pro-inflammatory mediators capable of causing inflammation, microcirculatory dysfunction and fibrosis of the underlying myocardium, thus impairing the relaxability of the left ventricle and increasing its filling pressure. In addition to representing a potential CV risk factor, emerging evidence shows that EAT may guide the therapeutic decision in diabetic patients as drugs such as metformin, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 inhibitors (SGLT2-Is), have been associated with attenuation of EAT enlargement.

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.

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.

Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence.

Type 2 diabetes mellitus (T2DM) is a worldwide major health burden and heart failure (HF) is the most common cardiovascular (CV) complication in affected patients. Therefore, identifying the best pharmacological approach for glycemic control, which is also useful to prevent and ameliorate the prognosis of HF, represents a crucial issue. Currently, the choice is between the new drugs sodium/glucose co-transporter 2 inhibitors that have consistently shown in large CV outcome trials (CVOTs) to reduce the risk of HF-related outcomes in T2DM, and metformin, an old medicament that might end up relegated to the background while exerting interesting protective effects on multiple organs among which include heart failure. When compared with other antihyperglycemic medications, metformin has been demonstrated to be safe and to lower morbidity and mortality for HF, even if these results are difficult to interpret as they emerged mainly from observational studies. Meta-analyses of randomized controlled clinical trials have not produced positive results on the risk or clinical course of HF and sadly, large CV outcome trials are lacking. The point of force of metformin with respect to new diabetic drugs is the amount of data from experimental investigations that, for more than twenty years, still continues to provide mechanistic explanations of the several favorable actions in heart failure such as, the improvement of the myocardial energy metabolic status by modulation of glucose and lipid metabolism, the attenuation of oxidative stress and inflammation, and the inhibition of myocardial cell apoptosis, leading to reduced cardiac remodeling and preserved left ventricular function. In the hope that specific large-scale trials will be carried out to definitively establish the metformin benefit in terms of HF failure outcomes, we reviewed the literature in this field, summarizing the available evidence from experimental and clinical studies reporting on effects in heart metabolism, function, and structure, and the prominent pathophysiological mechanisms involved.

HCC and Molecular Targeting Therapies: Back to the Future.

Hepatocellular carcinoma (HCC) is one of the leading causes of death from cancer in the world. Recently, the effectiveness of new antiviral therapies and the HBV vaccine have reduced HCC's incidence, while non-alcoholic steato-hepatitis is an emerging risk factor. This review focuses on antiangiogenic molecules and immune checkpoint inhibitors approved for HCC treatment and possible future approaches. Sorafenib was the first drug approved for the treatment of advanced HCC (aHCC) and it has been shown to increase survival by a few months. Lenvatinib, a multikinase inhibitor, has shown non-inferiority in survival compared with sorafenib and an improvement in progression-free survival (PFS). The combination of atezolizumab (an anti-PDL1 antibody) and bevacizumab (an anti-VEGF antibody) was the first drug combination approved for HCC, demonstrating improved survival compared with sorafenib (19.2 vs. 13.4 months). As a second line of therapy, three regimens (regorafenib, cabozantinib, and ramucirumab) have been approved for the treatment of aHCC after progression on sorafenib according to guidelines. Furthermore, nivolumab, pembrolizumab, and nivolumab plus ipilimumab have been approved by the FDA (2017, 2018, and 2020, respectively). Finally, immune target therapy, cancer vaccines, and epigenetic drugs represent three new possible weapons for the treatment of HCC.

Cardiovascular Benefits from Gliflozins: Effects on Endothelial Function.

Type 2 diabetes mellitus (T2DM) is a known independent risk factor for atherosclerotic cardiovascular disease (CVD) and solid epidemiological evidence points to heart failure (HF) as one of the most common complications of diabetes. For this reason, it is imperative to consider the prevention of CV outcomes as an effective goal for the management of diabetic patients, as important as lowering blood glucose. Endothelial dysfunction (ED) is an early event of atherosclerosis involving adhesion molecules, chemokines, and leucocytes to enhance low-density lipoprotein oxidation, platelet activation, and vascular smooth muscle cell proliferation and migration. This abnormal vascular phenotype represents an important risk factor for the genesis of any complication of diabetes, contributing to the pathogenesis of not only macrovascular disease but also microvascular damage. Gliflozins are a novel class of anti-hyperglycemic agents used for the treatment of Type 2 diabetes mellitus (T2DM) that selectively inhibit the sodium glucose transporter 2 (SGLT2) in the kidneys and have provoked large interest in scientific community due to their cardiovascular beneficial effects, whose underlying pathophysiology is still not fully understood. This review aimed to analyze the cardiovascular protective mechanisms of SGLT2 inhibition in patients T2DM and their impact on endothelial function.

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 implementing a Choosing Wisely educational intervention into clinical practice: The CW-SIMI study (a multicenter-controlled study).

OBJECTIVES: To evaluate the impact of an educational intervention based on the Italian Society of Internal Medicine Choosing Wisely (CW-SIMI) recommendations. DESIGN: Multicenter, interventional, controlled study. SETTING: Twenty-three acute-care hospital wards in Italy. PARTICIPANTS: 303 Physicians working in internal medicine wards. INTERVENTION: An online educational course. MAIN OUTCOMES: The rate of proton pump inhibitor (PPI) prescriptions, the number of days of central venous catheter (CVC) usage, and the duration of intravenous (IV) antibiotic prescriptions evaluated at one month (T1) and at six months (T2) after course completion. Patients admitted and discharged during a 30-day period before the educational intervention (T0, one year before T2) were considered the comparison group. RESULTS: A total of 232 physicians completed the course, while 71 did not attend the course. Data from 608, 662, and 555 patients were analyzed at T0, T1, and T2, respectively. The rate of PPI prescriptions declined at one month (RR: 0.67, 95% CI: 0.52-0.87, p = 0.0005) and at six months (RR: 0.62, 95% CI: 0.46-0.84, p = 0.003), and the number of days of CVC usage was reduced at six months (9.13 days at T0 vs. 5.52 days at T2, p = 0.007). The duration of IV antibiotic prescriptions displayed a decreasing trend (7.94 days at T0 vs. 7.42 days at T2, p = 0.081). CONCLUSIONS: A simple online educational intervention based on the CW-SIMI recommendations was associated with a clinically relevant reduction in the usage of PPIs and CVCs. Further studies are needed to confirm these findings and a possible benefit on patients' outcomes.

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.