Mean platelet volume (MPV) as new marker of diabetic macrovascular complications in patients with different glucose homeostasis : Platelets in cardiovascular risk.

BACKGROUND: Platelets play an important role in the development of cardiovascular disease (CVD). Mean platelet volume (MPV) is considered as biological marker of platelets activity and function. The aim of the present study was to evaluate MPV values and its possible correlation with arterial stiffness and subclinical myocardial damage, in normal glucose tolerance patients (NGT), in newly diagnosed type 2 diabetic (T2DM) patients and in individuals with pre-diabetes. METHODS: We enrolled 400 newly diagnosed hypertensive patients. All patients underwent an Oral Glucose Tolerance test (OGTT). Arterial stiffness (AS) was evaluated with the measurement of carotid-femoral pulse wave velocity (PWV), augmentation pressure (AP) and augmentation index (AI). Echocardiographic recordings were performed using an E-95 Pro ultrasound system. RESULTS: Among groups there was an increase in fasting plasma glucose (FPG) (p < 0.0001), fasting plasma insulin (FPI) (p < 0.0001), high sensitivity c reactive protein (hs-CRP) levels (p < 0.0001) and a decrease in renal function as demonstrated by e-GFR values (p < 0.0001). From the NGT group to the T2DM group there was a rise in MPV value (p < 0.0001). Moreover, in the evaluation of arterial stiffness and subclinical myocardial damage, MPV showed a positive correlation with these parameters. CONCLUSIONS: In the present study we highlighted that MPV is significantly increased, not only in newly diagnosed T2DM patients, but also in early stage of diabetes, indicating that subjects with pre-diabetes present increased platelets reactivity. Moreover, our results suggest that MPV is associated with increased arterial stiffness and subclinical myocardial damage, indicating MPV as new marker of CV risk.

Appropriateness of direct oral anticoagulant prescribing in older subjects with atrial fibrillation discharged from acute medical wards.

AIMS: Knowledge on the prescriptive practice of direct oral anticoagulants (DOACs) in older subjects with atrial fibrillation (AF) hospitalized in acute medical wards is limited. This study aimed to evaluate the prevalence and appropriateness of DOAC prescriptions in hospitalized older subjects with AF, discharged from acute medical wards. METHODS: We analysed a cohort of 609 subjects with AF, aged ≥65 years (mean age 85 years) enrolled from 39 geriatric and nephrology wards in Italy. DOAC prescriptive appropriateness was evaluated according to the summary of product characteristics (smPC), 2019 Beers and STOPP criteria, and drug-drug interactions (DDIs). RESULTS: At hospital discharge, 33% of patients with AF were prescribed with DOAC, 26% with vitamin-K antagonist, while 41% did not receive any anticoagulant. Among subjects on DOAC therapy, 31% presented a violation of the smPC criteria (mainly underdosage-17%), while 48% and 18% presented a Beers/STOPP inappropriate prescription, or a DDI, respectively. Older age, lower body mass index (BMI), cancer and higher estimated glomerular filtration rate (eGFR) were independently associated with DOAC underdosage or missed prescription (age: adjusted odds ratio [aOR] 1.06, 95% confidence interval [95% CI] 1.00-1.12 for underdosage; eGFR: aOR 1.04, 95% CI 1.02-1.07 for underdosage; BMI: aOR 0.95, 95% CI 0.91-0.99 for missed prescription; cancer: aOR 1.93, 95% CI 1.19-3.13 for missed prescription). CONCLUSIONS: This study showed a suboptimal DOAC prescriptive practice in older in-patients, with frequent missed prescription and DOAC underdosage. Contrary to current recommendations, physicians appear overly concerned by bleeding risk in real-life older and frailer subjects. Strategies should be developed to promote appropriate DOAC prescription in the hospital setting.

Overexpression of BAG3 (Bcl2-associated athanogene 3) in serum and skin of patients with systemic sclerosis.

OBJECTIVES: BAG3 (Bcl2-associated athanogene3) is able to induce the transformation of cancer-associated fibroblasts to alpha smooth muscle actin (a-SMA) positive (+) myofibroblasts. In systemic sclerosis (SSc), a-SMA+ myofibroblasts also play an important role in the progression of fibrosis in the skin and involved internal organs. The aim of the study was to investigate whether BAG3 is overexpressed in SSc and may be a biomarker of fibrogenesis. METHODS: BAG3 serum levels were measured in 106 patients with SSc, 47 with the limited (lc) and 59 the diffuse (dc) SSc, and in age- and sex-matched healthy controls (HC). BAG3 levels were then compared according to their clinical subset, nailfold video-capillaroscopic (NVC) patterns, interstitial lung disease (ILD, and correlated with modified Rodnan skin score (mRSS) and global disease activity. BAG3 expression was also investigated in skin biopsies of 8 dcSSc patients. RESULTS: BAG3 serum levels were significantly higher in dcSSc (143.3 pg/mL, 95%CI 78-208.5) than in HC (0.68 pg/mL, 95%CI 0.13-1.23), and were significantly higher in patients with late NVC pattern and ILD but did not correlate with disease activity and mRSS. Of note, BAG3 was strongly expressed in the skin biopsies of dcSSc patients. CONCLUSIONS: BAG3 is overexpressed in dcSSc patients and may contribute to skin and organ fibrosis by prompting the transition of fibroblasts into myofibroblasts and increasing their survival. Thus, BAG3 may play an important role in SSc fibrotic pathogenesis and be a potential biomarker of fibrosis. Further research on its role as a therapeutic target is warranted.

Significant nailfold capillary loss and late capillaroscopic pattern are associated with pulmonary arterial hypertension in systemic sclerosis.

OBJECTIVES: To evaluate differences in nailfold videocapillaroscopy (NVC) findings between systemic sclerosis-SSc patients with and without a diagnosis of pulmonary arterial hypertension (PAH). METHODS: 110 SSc patients were enrolled in this cross-sectional, case-control, multi-centre study. Patients were divided into cases (SSc-PAH confirmed by right hearth catheterization-RHC) and controls (SSc-nonPAH with low probability of PAH). NVC patterns (early, active, and late) and morphological parameters (microvascular density, non-specific abnormalities, giant capillaries, micro-haemorrhages, avascular areas) were considered using a semiquantitative scoring system. RESULTS: SSc-PAH patients showed higher frequencies of late pattern (p < 0.01), non-specific abnormalities (p < 0.01), lower capillary density (p < 0.01), higher avascular areas (p < 0.01), and a higher mean NVC score (p < 0.01). Contrarily, the early/active pattern (p < 0.01) and a higher rate of micro-haemorrhages (p = 0.04) were more frequent in non-PAH patients. By the multivariate analysis, SSc-PAH patients, compared to non-PAH, had more non-specific abnormalities (27/55, 49.1% vs 10/55, 18.2%, adjusted OR: 16.89, 95%CI: 3.06-93.16), a lower capillary density (grade 3, 20/55, 36.4% vs 5/55, 9.1%, adjusted OR: 38.33, 95%CI: 2.34-367.80), and avascular areas (18/55, 32.7% vs 10/55, 18.2%, adjusted OR: 16.90, 95%CI: 2.64-44.35). A correlation was found between the mean pulmonary arterial pressure-mPAP and avascular areas (p < 0.01), capillary density (p < 0.01), and non-specific abnormalities (p < 0.01). A clinical model including the NVC variables may be able to predict the diagnosis of PAH. CONCLUSIONS: Our results indicate that the distinctive peripheral microcirculatory injury of SSc, i.e capillary loss and morphological abnormalities, appear more severe and pronounced in patients with SSc-PAH.

Pharmacological treatment of type 2 diabetes in elderly patients with heart failure: randomized trials and beyond.

Heart failure (HF) and type 2 diabetes mellitus (T2DM) represent two important public health problems, and despite improvements in the management of both diseases, they are responsible for high rates of hospitalizations and mortality. T2DM accelerates physiological cardiac aging through hyperglycemia and hyperinsulinemia. Thus, HF and T2DM are chronic diseases widely represented in elderly people who often are affected by numerous comorbidities with important functional limitations making it difficult to apply the current guidelines. Several antidiabetic drugs should be used with caution in elderly individuals with T2DM. For instance, sulfonylureas should be avoided due to the risk of hypoglycemia associated with its use. Insulin should be used with caution because it is associated with higher risk of hypoglycemia, and may determine fluid retention which can lead to worsening of HF. Thiazolindinediones should be avoided due to the increased risk of fluid retention and HF. Biguanides may lead to a slightly increased risk of lactic acidosis in particular in elderly individuals with impaired renal function. Dipeptidyl peptidase 4 (DPP-4) inhibitors are safe having few side effects, minimal risk of hypoglycemia, and a neutral effect on cardiovascular (CV) outcome, even if it has been reported that saxagliptin treatment is associated with increased risk of hospitalizations for HF (hHF). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown a CV protection without a significant reduction in hHF. On the other hand, sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown a significant improvement in CV outcome, with a strong reduction of hHF and a positive impact on renal damage progression. However, it is necessary to consider the possible some side effects related to their use in elderly individuals including hypotension, bone fractures, and ketoacidosis.It is important to remark that elderly patients, in particular the very elderly, are not sufficiently represented in the trials; thus, the management and treatment of elderly diabetic patients with HF should be mainly based on the integration of scientific evidence with clinical judgment and patients' condition, with respect to the dignity and quality of life.

Association between right ventricular dysfunction and adverse cardiac events in mild COPD patients.

BACKGROUND: Lung hyperinflation and systemic inflammation are currently believed to be the most important causes of right heart alterations in chronic obstructive pulmonary disease (COPD) patients. A multicentre observational study was performed to assess the morphological and functional parameters of right ventricle (RV) in COPD subjects, as well as to evaluate the potential prognostic impact on the development of major cardiovascular adverse events (MACEs). METHODS: For this retrospective study, from 1 January 2010 to 31 December 2021, we enrolled COPD patients on the basis of their airflow limitation. In particular, we selected subjects spanning across GOLD 1 and 2 functional stages. Clinical, laboratory and functional parameters were collected at baseline. Echocardiography was routinely performed in all COPD patients. RV dysfunction was defined on the basis of tricuspid annular plane systolic excursion (TAPSE) values. MACE occurrence (non-fatal ischemic stroke, non-fatal myocardial infarction, cardiac revascularization or coronary bypass surgery and cardiovascular death) was evaluated during a median follow-up of 55 (36-72) months. RESULTS: Among the 749 enrolled patients, 408 subjects had a TAPSE value ≥20 mm, while the remaining 341 had a TAPSE value <20 mm. In patients with TAPSE ≥20 mm the observed MACEs were 1.9 events/100 patient-year, while in the group with a worse right heart function there were 4.2 events/100 patient-year (p < .0001). The multivariate analysis model confirmed the association between RV dysfunction and MACE. Indeed, a 1-mm increase in TAPSE value and the intake of long-acting ß2 -receptor agonists (LABA)/long-acting muscarinic antagonist (LAMA) inhaled therapy were protective factors for the onset of MACE, while the presence of diabetes mellitus and high values of both uric acid (UA) and systolic pulmonary arterial pressure (S-PAP) enhanced the risk of MACE in study participants. CONCLUSIONS: The results of this study showed that in patients with mild COPD there is an association between right heart dysfunction and the risk of MACE during follow-up.

Serum proprotein convertase subtilisin/Kexin type 9 and vascular disease in type 2 diabetic patients.

BACKGROUND: Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) levels have been suggested as novel atherosclerotic biomarker. PCSK9 plays important roles in the pathogenesis of atherosclerosis by regulating the degradation of low-density lipoprotein receptor as well as different inflammatory pathways. Considering the important prognostic role of arterial stiffness in cardiovascular disease (CVD), the aim of the study is to investigate the correlation between PCSK9 levels and arterial stiffness in a cohort of diabetic patients, without previous CV events. METHODS: This cross-sectional analysis enrolled 401 Caucasian patients with type II diabetes mellitus (T2DM). PCSK9 levels were measured by ELISA test, arterial stiffness was estimated by measuring carotid-femoral pulse wave velocity (PWV). RESULTS: Patients were divided in three tertiles according to increasing value of PCSK9. From the I to the III tertiles, there was a significant increase in high sensitivity C-reactive protein (hs-CRP), fibrinogen and white blood cells (WBC) and a reduction in estimated glomerular filtration rate (e-GFR). Patients with higher levels of PCSK9 presented increased systolic, diastolic blood pressure, pulse pressure and PWV. PWV was significantly and directly correlated with PCSK9, fibrinogen, age, BMI and PP, and indirectly correlated with diet, lifestyle and e-GFR. Serum PCSK9 was the major predictor of PWV, justifying a 16.9% of its variation. CONCLUSION: Our study demonstrates a close association between circulating PCSK9 levels and PWV in T2DM subjects without previous CV events even after adjusting for well-known CV risk factor and pharmacological medications. Serum PCSK9 could be a useful biomarker for CV risk stratification in diabetic subjects.

One-hour post-load glucose and subclinical left atrial myocardial dysfunction in hypertensive patients.

BACKGROUND: Recently, studies demonstrated that normal glucose-tolerant subjects (NGT) with 1-h post-load plasma glucose value ≥155 mg/dL during oral glucose tolerance test (OGTT) (NGT ≥ 155) present an impaired cardio-metabolic profile, with subclinical myocardial damage. Atrial morphological and functional alterations, closely related to diastolic dysfunction, are important predictors of atrial fibrillation (AF), cardiovascular (CV) events and mortality in the entire population as well as in diabetic patients. The aim of our study was to evaluate subclinical atrial myocardial damage, assessed with speckle tracking echocardiography, in NGT≥155 mg/dL patients, comparing to NGT < 155 mg/dL subjects, impaired glucose tolerant (IGT) individuals and patients with newly diagnosed type 2 diabetes (T2DM). METHODS: We enrolled 229 Caucasian patients. All subjects underwent anthropometrical and haemodynamic parameters evaluation, OGTT, advanced Colour-Doppler echocardiography with evaluation of main atrial and ventricular parameters. RESULTS: As expected, from first to the fourth group there was a worsening of the metabolic profile as attested by fasting, 1- and 2-h post-load plasma glucose levels, during OGTT. Moreover, from NGT < 155 to T2DM group there was an impairment in reservoir and pump atrial function (PALS and PACS, respectively) (p < .0001). CONCLUSION: Present data demonstrated for the first time that NGT≥155 subjects present subclinical atrial dysfunction. These results may be clinically relevant because they highlight how atrial myopathy occurs early in pre-diabetes stage regardless of fibrotic and morphological alterations of the ventricular myocardium.

Ranolazine Attenuates Brain Inflammation in a Rat Model of Type 2 Diabetes.

Recent studies suggest a pathogenetic association between metabolic disturbances, including type 2 diabetes (T2DM), and cognitive decline and indicate that T2DM may represent a risk factor for Alzheimer's disease (AD). There are a number of experimental studies presenting evidence that ranolazine, an antianginal drug, acts as a neuroprotective drug. The aim of the present study was to evaluate the effects of ranolazine on hippocampal neurodegeneration and astrocytes activation in a T2DM rat model. Diabetes was induced by a high fat diet (HFD) and streptozotocin (STZ) injection. Animals were divided into the following groups: HFD/STZ + Ranolazine, HFD/STZ + Metformin, HFD/STZ + Vehicle, NCD + Vehicle, NCD + Ranolazine and NCD + Metformin. The presence of neurodegeneration was evaluated in the hippocampal cornus ammonis 1 (CA1) region by cresyl violet staining histological methods, while astrocyte activation was assessed by western blot analysis. Staining with cresyl violet highlighted a decrease in neuronal density and cell volume in the hippocampal CA1 area in diabetic HFD/STZ + Vehicle rats, while ranolazine and metformin both improved T2DM-induced neuronal loss and neuronal damage. Moreover, there was an increased expression of GFAP in the HFD/STZ + Vehicle group compared to the treated diabetic groups. In conclusion, in the present study, we obtained additional evidence supporting the potential use of ranolazine to counteract T2DM-associated cognitive decline.

Association between non-dipping blood pressure pattern and different glucometabolic profile during oral glucose tolerance test.

It is known that, a not physiological blood pressure (BP) circadian pattern has been associated with increased risk of organ damage and cardiovascular (CV) event. The aim of this study was to assess the association between circadian BP pattern and glucometabolic phenotypes occurring after oral glucose tolerance test (OGTT). We recruited 810 hypertensive Caucasian patients. All participants underwent to OGTT, laboratory test and 24-h ambulatory BP monitoring (ABPM). The analysis of collected data allowed classifying patients based on nocturnal BP profiles into four categories: dippers, non-dippers, extreme dippers, and reverse dippers. Considering the dipping pattern, the proportion of non-dippers in normal glucose tolerance patients with 1-h glucose ≥ 155 mg/dL (NGT ≥ 155) (36.4%) was higher than NGT < 155 (29.6%) and impaired glucose tolerance (IGT) (34.8%), but lower than type 2 diabetes group (T2DM) (52.6%) (p = 0.001). The proportion of dippers was lower in NGT ≥ 155 (47%) and T2DM (34.6%), when compared with NGT < 155 (53.8%) and IGT (51.2%) (p = 0.017). From logistic regression analysis, 1-h glucose ≥ 155 increased the risk of a pathological nocturnal drop in BP by 74%, (OR = 1.740, 95% CI 1.254-2.415, p < 0.0001). In addition, the improvement in 1 unit of Matsuda was responsible for a 3.5% risk decrease (OR = 0.965, 95% CI 0.958-0.971, p < 0.0001), while e-GFR determined a 0.9% risk reduction of nocturnal BP drop (OR = 0.991, 95% CI 0.984-0.999, p = 0.020). Our data demonstrated the existence, in newly diagnosed hypertensive patients, of an association between circadian BP profile and altered glycemic response during OGTT, in particular NGT ≥ 155 subjects are associated with a non-dipper BP pattern, this is clinically relevant because may explain, at least in part, the increased CV risk in this setting of patients.

Sex-based differences in the comprehensive geriatric assessment in elderly hospitalized patients with non-valvular atrial fibrillation.

Atrial fibrillation (AF) represents the most common supraventricular arrhythmia, with a prevalence of 1-3 % in the world population. Growing evidences show that AF plays an important role as a risk factor for the development of cognitive impairment (CoI) and dementia, depression and functional limitation. The purpose of the study is to evaluate, in a large cohort of elderly hospitalized patients with nonvalvular AF (NVAF) on direct oral anticoagulants (DOACs) therapy, the prevalence of CoI, depression, and functional limitation, and to assess the different variables that may be detrimental or protective on the risk of CoI or functional limitation. 1004 elderly patients were enrolled, 384 men and 620 women, with a mean age of 84±7.1 years. The two groups were comparable for the main study variables, except for age, prevalence of hypertension and CKD, which were higher in women, while ischemic heart disease was higher in men. In addition, the two groups differed in the CHA2DS2VASc score 5.3 ± 1.3 vs 4.2 ± 1.4 pts (p < 0.0001) and HAS-BLED score 2.5 ± 0.7 vs 2.3 ± 0.8 pts (p = 0.009) that were significantly higher in women. Our study revealed that in a cohort of elderly patients hospitalized with AF taking DOACs, CoI and disability are widely represented, and female sex increases the risk of being affected by CoI by about 3-fold, while improvement of functional limitations reduce this risk by about 15 %. In addition, CoI and depressive symptoms increase the risk of functional impairment about 2-fold and 28 % respectively, while antihypertensive and anti-diabetic therapy reduce this risk.

Cardiovascular Biomarkers in Cardio-Oncology: Antineoplastic Drug Cardiotoxicity and Beyond.

Serum biomarkers represent a reproducible, sensitive, minimally invasive and inexpensive method to explore possible adverse cardiovascular effects of antineoplastic treatments. They are useful tools in risk stratification, the early detection of cardiotoxicity and the follow-up and prognostic assessment of cancer patients. In this literature review, we aim at describing the current state of knowledge on the meaning and the usefulness of cardiovascular biomarkers in patients with cancer; analyzing the intricate relationship between cancer and cardiovascular disease (especially HF) and how this affects cardiovascular and tumor biomarkers; exploring the role of cardiovascular biomarkers in the risk stratification and in the identification of chemotherapy-induced cardiotoxicity; and providing a summary of the novel potential biomarkers in this clinical setting.

Effect of SGLT2-Inhibitors on Polygraphic Parameters in Elderly Patients Affected by Heart Failure, Type 2 Diabetes Mellitus, and Sleep Apnea.

Obstructive sleep apneas (OSAs) and central sleep apneas (CSAs) are the most common comorbidities in Heart Failure (HF) that are strongly associated with all-cause mortality. Several therapeutic approaches have been used to treat CSA and OSA, but none have been shown to significantly improve HF prognosis. Our study evaluated the effects of a 3-months treatment with sodium-glucose cotransporter type 2 inhibitor (SGLT2i) on polygraphic parameters in patients with sleep apnea (SA) and HF, across the spectrum of ejection fraction, not treated with continuous positive air pressure (CPAP). A group of 514 consecutive elderly outpatients with HF, type 2 diabetes mellitus (T2DM) and SA, eligible for treatment with SGLT2i, were included in the investigation before starting any CPAP therapy. The two groups were compared with the t-test and Mann-Whitney test for unpaired data when appropriate. Then, a simple logistic regression model was built using 50% reduction in AHI as the dependent variable and other variables as covariates. A multivariate stepwise logistic regression model was constructed using the variables that linked with the dependent variable to calculate the odds ratio (OR) for the independent predictors associated with the reduction of 50% in AHI. The treated group experienced significant improvements in polygraphic parameters between baseline values and follow-up with reduction in AHI (28.4 ± 12.9 e/h vs. 15.2 ± 6.5 e/h; p < 0.0001), ODI (15.4 ± 3.3 e/h vs. 11.1 ± 2.6 e/h; p < 0.0001), and TC90 (14.1 ± 4.2% vs. 8.2 ± 2.0%; p < 0.0001), while mean SpO2 improved (91. 3 ± 2.3 vs. 93.8 ± 2.5); p < 0.0001. These benefits were not seen in the untreated population. The use of SGLT2i in patients suffering from HF and mixed-type SA not on CPAP therapy significantly contributes to improving polygraphic parameters.

Prognostic role of serum albumin levels in patients with chronic heart failure.

BACKGROUND: Hypoalbuminemia is common in heart failure (HF) patients; however, there are no data regarding the possible long-term prognostic role of serum albumin (SA) in the younger population with chronic HF without malnutrition. The aim of this study was to examine the long-term prognostic role of SA levels in predicting major adverse cardiac events (MACE) in middle-aged outpatients with chronic HF. METHODS: In the present retrospective analysis, 378 subjects with HF were enrolled. MACE (non-fatal ischemic stroke, non-fatal myocardial infarction, cardiac revascularization or coronary bypass surgery, and cardiovascular death), total mortality, and HF hospitalizations (hHF) occurrence were evaluated during a median follow-up of 6.1 years. RESULTS: In all population, 152 patients had a SA value < 3.5 g/dL and 226 had a SA value ≥ 3.5 g/dL. In patients with SA ≥ 3.5 g/dL, the observed MACE were 2.1 events/100 patient-year; while in the group with a worse SA levels, there were 7.0 events/100 patient-year (p < 0.001). The multivariate analysis model confirmed that low levels of SA increase the risk of MACE by a factor of 3.1. In addition, the presence of ischemic heart disease, serum uric acid levels > 6.0 mg/dL, chronic kidney disease, and a 10-year age rise, increased the risk of MACE in study participants. Finally, patients with SA < 3.5 g/dl had a higher incidence of hHF (p < 0.001) and total mortality (p < 0.001) than patients with SA ≥ 3.5 g/dl. CONCLUSIONS: Patients with chronic HF that exhibits low SA levels show a higher risk of MACE, hHF and total mortality.

Effect of dual glucose-dependent insulinotropic peptide/glucagon-like peptide-1 receptor agonist on weight loss in subjects with obesity.

The occurrence of obesity is an increasing issue worldwide, especially in industrialized countries. Weight loss is important both to treat obesity and to prevent the development of complications. Currently, several drugs are used to treat obesity, but their efficacy is modest. Thus, new anti-obesity treatments are needed. Recently, there has been increased interest in the development of incretins that combine body-weight-lowering and glucose-lowering effects. Therefore, a new drug that simultaneously coactivates both the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R) has been developed. Tirzepatide, the first in this class, improves glycemic control by increasing insulin sensitivity and lipid metabolism as well as by reducing body weight. Combining the activation of the two receptors, greater improvement of ß-cell function offers more effective treatment of diabetes and obesity with fewer adverse effects than selective GLP-1R agonists. In the present review, we discuss the progress in the use of GIPR and GLP-1R coagonists and review literature from in vitro studies, animal studies, and human trials, highlighting the synergistic mechanisms of tirzepatide.

Clinical and Functional Effects of Inhaled Dual Therapy Umeclidinium/Vilanterol in Patients with Chronic Obstructive Pulmonary Disease: A Real-Life Study.

Background: The pharmacological association umeclidinium/vilanterol (UMEC/VI) allows to implement a very effective dual bronchodilation in chronic obstructive pulmonary disease (COPD), thus optimizing bronchodilating therapy. Methods: The main purpose of our real-world observational study was to evaluate in COPD patients the effects of UMEC/VI on lung function and respiratory symptoms. Functional and clinical parameters were assessed at baseline, and after 52 weeks of treatment with this combined double inhaled therapy. Results: We enrolled 110 subjects suffering from COPD. A 12-month UMEC/VI treatment induced significant improvements in total lung capacity (TLC) (p < 0.05), and residual volume (RV) (p < 0.0001). Pulmonary deflation was paralleled by significant increases of forced expiratory volume in one second (FEV1) (p < 0.0001), forced vital capacity (FVC) (p < 0.01), forced expiratory flow between 25% and 75% of FVC (FEF25-75) (p < 0.0001) and diffusion capacity of the lung (DLCOcSB) (p < 0.05). In addition, in the same period, we also observed significant reductions of airway resistance including total resistance (Rtot) (p < 0.0001) and specific effective resistance (sReff) (p < 0.0001). Other improvements were detected with regard to modified British Medical Research Council (mMRC) questionnaire score (p < 0.0001), COPD Assessment Test (CAT) score (p < 0.0001), and COPD exacerbation rate (p < 0.0001). In particular, the reported changes of mMRC/CAT scores and COPD exacerbation numbers were significantly correlated with UMEC/VI-induced modifications of TLC, RV, FVC and FEV1. Conclusion: In conclusion, our study corroborates in a real-life context the effectiveness of UMEC/VI in COPD treatment. Indeed, our broad investigational strategy has allowed to better characterize the functional mechanisms underpinning the therapeutic properties of UMEC/VI association.

Short term effect of sacubitril/valsartan on comprehensive geriatric assessment in chronic heart failure: a real life analysis.

Sacubitril/Valsartan (Sac-Val) has improved clinical prognosis in patients affected by heart failure (HF) with reduced ejection fraction (HFrEF). Comorbidities have a crucial impact on clinical presentation and prognosis in HF patients. Cognitive impairment (CoI) and Depression are a very common comorbidity in patients with HF and is widely recognized as a specific determinant of chronic disability, and HF patients with poor physical functional performance in Short physical performance battery (SPPB) showed a worse prognosis. The aim of the present study was to evaluate the potential effects of Sac-Val on functional, humoral, and cognitive aspects, evaluated by performing comprehensive geriatric assessment (CGA), in a cohort of elderly HFrEF. We studied 61 patients (51 men and 10 women, mean age 76.4 ± 5.1 years) suffering from HFrEF. After 6 months follow-up, we observed a significant improvement in humoral and functional parameters of CGA, renal function, NTpro-BNP levels and echocardiographic parameters. In the whole population, multivariate analysis shows that changes of Cardiac Index, NT-proBNP and Respiratory rate contributed for 26.0%, 9.7% and 4.8% to GDS variability, respectively, and the whole model accounted for a 41.1% of GDS variation; moreover changes of Global longitudinal strain, estimated glomerular filtration rate, Cardiac Index and BMI contributed for 23.9%, 11.7%, 5.4% and 4.0% to SPPB variability, respectively, and the whole model accounted for a 45% of SPPB variation. This represents the first real-world study carried out in an elderly population suffering from chronic HFrEF with numerous comorbidities, in which treatment with Sac-Val for 6 months induced important improvements in clinical, humoral, hemodynamic, and functional outcomes, without adverse effects on cognitive performance.

Effects of continuous positive airway pressure on comprehensive geriatric assessment and cognitive function in elderly patients with obstructive sleep apnea syndrome.

Obstructive sleep apnea syndrome (OSAS) can lead to cognitive impairment and depression affecting memory, attention, and executive functions. Continuous positive airway pressure (CPAP) treatment seems to be able to revert changes in brain networks and neuropsychological tests correlated to OSAS. The aim of the present study was to evaluate the effects of a 6-month treatment with CPAP on functional, humoral and cognitive parameters in a cohort of elderly OSAS patients with several comorbidities. We enrolled 360 elderly patients suffering from moderate to severe OSAS and indication for nocturnal CPAP. At baseline the Comprehensive Geriatric Assessment (CGA) revealed a borderline Mini-Mental State Examination (MMSE) score that improved after 6-month treatment with CPAP (25.3 ± 1.6 vs 26 ± 1.5; p < 0.0001), as well as the Montreal Cognitive Assessment (MoCA) showed a mild improvement (24.4 ± 2.3 vs 26.2 ± 1.7; p < 0.0001). Moreover, functionality activities increased after treatment, as documented by a short physical performance battery (SPPB) (6.3 ± 1.5 vs 6.9 ± 1.4; p < 0.0001). Reduction of the Geriatric Depression Scale (GDS) from 6.0 ± 2.5 to 4.6 ± 2.2 (p < 0.0001) was also detected. Changes of homeostasis model assessment (HOMA) index, oxygen desaturation index (ODI), sleep-time spent with saturation below 90% (TC90), peripheral arterial oxyhaemoglobin saturation (SpO2), apnea-hypopnea index (AHI) and estimation of glomerular filtration rate (eGFR), contributed, respectively, to 27.9%, 9.0%, 2.8%, 2.3%, 1.7% and 0.9% of MMSE variability for a total of 44.6% of MMSE variations. GDS score changes were due to the improvement of AHI, ODI and TC90, respectively, for 19.2%, 4.9%, 4.2% of the GDS variability, cumulative responsible for 28.3% of GDS modifications. The present real-world study shows that CPAP treatment is able to improve cognition and depressive symptoms in OSAS elderly patients.

New potential biomarkers for early chronic kidney disease diagnosis in patients with different glucose tolerance status.

Background: The purpose of the present study was to investigate the role of oxidative stress, platelet activation, and endocan levels in renal dysfunction in normal glucose tolerance (NGT) patients with 1-h plasma glucose values ≥155 mg/dl (NGT ≥ 155), compared to NGT < 155, impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM) newly diagnosed subjects. We enlisted 233 patients subjected to an oral glucose tolerance test (OGTT). Materials and methods: The serum levels of platelet activation (glycoprotein VI and sP-selectin), oxidative stress biomarkers (8-isoprostane and Nox-2), and endocan were evaluated using an ELISA test. Results: Among NGT < 155 patients and the T2DM group, there was a statistically significant increase in 8-isoprostane (p < 0.0001), Nox-2 (p < 0.0001), glycoprotein VI (p < 0.0001), and sP-selectin (p < 0.0001) serum levels. Higher serum endocan levels were found with the worsening of metabolic profile (p < 0.0001); specifically, NGT ≥ 155 patients presented higher serum endocan values when compared to NGT < 155 patients (p < 0.0001). From the multivariate linear regression analysis, 1-h glucose resulted in the major predictor of estimated glomerular filtration rate (e-GFR) justifying 23.6% of its variation (p < 0.0001); 8-isoprostane and Nox-2 added respectively another 6.0% (p < 0.0001) and 3.2% (p = 0.001). Conclusion: Our study confirmed the link between 1-h post-load glucose ≥155 mg/dl during OGTT and the possible increased risk for chronic kidney disease (CKD) in newly diagnosed patients. The novelty is that we demonstrated a progressive increase in oxidative stress, platelet activation, and serum endocan levels with the worsening of metabolic profile, which becomes evident early during the progression of CKD.

Medium-term and long-term renal function changes with direct oral anticoagulants in elderly patients with atrial fibrillation.

Objective: Atrial Fibrillation (AF) and chronic kidney disease frequently coexist in the elderly. Warfarin-like drugs (WLDs) may be associated with a relatively greater decrease of estimated glomerular filtration rate (eGFR) as compared to direct oral anticoagulants (DOACs), but there is no evidence on the medium- and long-term changes. To further elucidate this issue in elderly patients with AF, we investigated the renal function deterioration in the two groups of the study (DOACs or WLDs). Patients and Methods: A total of 420 AF patients were enrolled (mean age: 77.0 ± 6.0 years; 136 on WLDs and 284 on DOACs). These patients underwent three eGFR measurements during the follow-up period. The between-arms difference of eGFR decline over time was investigated by Linear Mixed Models and group-based trajectory model analyses. Results: In the whole study cohort, after a median follow-up of 4.9 years (interquartile range: 2.7-7.0 years), eGFR decreased from 67.4 ± 18.2 to 47.1 ± 14.3 mL/min/1.73 m2 (p < 0.001). Remarkably, patients on DOACs experienced a significantly smaller eGFR decline than WLDs patients (-21.3% vs. -45.1%, p < 0.001) and this was true both in the medium-term (-6.6 vs. -19.9 mL/min/1.73 m2) and in the long-term (-13.5 versus -34.2 mL/min/1.73 m2) period. After stratification into five subgroups according to trajectories of renal function decline over time, logistic regression showed that DOACs patients had from 3.03 to 4.24-fold greater likelihood to belong to the trajectory with less marked eGFR decline over time than WLDs patients. Conclusion: Elderly patients with AF on treatment with DOACs had a relatively smaller decline of eGFR over time compared to those on treatment with WLDs. This is consistent with what was partly reported in the literature.