Redefining diabetes mellitus treatments according to different mechanisms beyond hypoglycaemic effect

Early epidemiologic studies in type 2 diabetes suggested that the long-term risk of microvascular and macrovascular complications increase progressively as glucose concentrations rise, inspiring the pursuit of near euglycaemia as a means of preventing these complications in type 1 and type 2 diabetes. Evidence emerging over the past decade, however, showed that the aggressive efforts often needed to achieve low HbA1c levels can ultimately lead to worse clinical outcomes, greater risk of severe hypoglycaemia, and higher burden of treatment. The acknowledgment of the disappointing results obtained with therapies aimed exclusively at improving glycaemic control has led in recent years to a substantial paradigm shift in the treatment of the diabetic patient. The results obtained first with GLP-1RAs and more recently even more with SGLT2i on mortality and CV events have made it clear how other mechanisms, beyond the hypoglycaemic effect, are at the basis of the benefits observed in several cardiovascular outcome trials. And as evidence of the great revolution of thought we are experiencing, there is the recognition of gliflozins as drugs for the treatment not only of diabetic patients but also of non-diabetic patients suffering from HF, as reported in the latest ESC/HFA guidelines. Surely, we still have a lot to understand, but it is certain that this is the beginning of a new era

Clinical utility of tolvaptan in the management of hyponatremia in heart failure patients

Hyponatremia is an electrolyte disorder frequently observed in several clinical settings and common in hospitalized patients with decompensated heart failure (HF). It is caused by deregulation of arginine vasopressin (AVP) homeostasis associated with water retention in hypervolemic or in euvolemic states. While hypervolemic hypotonic hyponatremia is also seen in advanced liver cirrhosis, renal failure, and nephrotic syndrome, the bulk of evidence associating this electrolyte disorder to increasing morbidity and mortality can be found in the HF literature. Hospitalized HF patients with low serum sodium concentration have lower short-term and long-term survival, longer hospital stay and increased readmission rates. Conventional therapeutic approaches, ie, restriction of fluid intake, saline and diuretics, can be effective, but often the results are unpredictable. Recent clinical trials have demonstrated the effectiveness of nonpeptide AVP receptor antagonists (vaptans) in the treatment of hyponatremia. The vaptans induce aquaresis, an electrolyte-sparing excretion of free water resulting in the correction of serum sodium concentrations and plasma osmolality, without activation of the renin-angiotensin-aldosterone system (RAAS) or changes in renal function and blood pressure. Further prospective studies in a selected congestive HF population with hyponatremia, using clinical-status titrated dose of tolvaptan, are needed to determine whether serum sodium normalization will be translated into a better long-term prognosis. This review will focus on recent clinical trials with tolvaptan, an oral V2 receptor antagonist, in HF patients. The ability of tolvaptan to safely increase serum sodium concentration without activating the RAAS or compromising renal function and electrolyte balance makes it an attractive agent for treating hyponatremic HF patients

N-3 Polyunsaturated Fatty Acids and Their Role on Cardiovascular System

The interest in n-3 polyunsaturated fatty acids (n-3 PUFAs), their favorable effects on the cardiovascular (CV) risk profile and prevention of CV events has been growing over the years, leading to their recommendation for secondary prevention in post myocardial infarction and hypertriglyceridemia. However, years later conflicting results provided by clinical trials have generated some doubts about their CV benefits, leading to a limited indication for the treatment of hypertriglyceridemia. Only recently, after the REDUCE-IT Trial results on CV events and mortality, n-3 PUFAs have recovered an indication in the international guidelines for hypertriglyceridemia in patients with Atherosclerotic Cardiovascular Disease (ASCVD) or with type 2 diabetes mellitus (T2DM) and other CV risk factors, already on statin therapy. Multiple beneficial CV effects have been highlighted, in addition to the well-known lipid-lowering function, such as anti-inflammatory, anti-thrombotic and endothelial function protective properties. Three formulations of n-3 PUFAs are currently available on the market, sharing some pharmacokinetic and pharmacodynamic characteristics, but also exhibiting peculiar mechanisms. Three major clinical trials evaluated the efficacy and safety of different formulations of n-3 PUFA: JELIS, REDUCE-IT and STRENGTH, with controversial results attributable to various factors. For the future, it could be useful to perform comparative studies between different formulations and placebo, in order to clarify these doubts

Non-compaction of the ventricular myocardium

Non-compaction of the left ventricle (LVNC) is a disorder of endomyocardial morphogenesis that results in multiple trabeculations in the left ventricular (LV) myocardium. This rare disorder is characterized by an excessively prominent trabecular meshwork and deep intratrabecular recesses. This idiopathic cardiomyopathy is characterized by an altered structure of the myocardial wall as a result of intrauterine arrest of compaction of the myocardial fibers in the absence of any coexisting congenital lesion. It can be associated with neuromuscular disorders and can co-exist with other cardiac malformations, and it is accompanied by depressed ventricular function, systemic embolism and ventricular arrhythmia. Echocardiography is the method of choice for diagnosing LVNC, but the correct diagnosis is often missed or delayed due to a lack of knowledge concerning this uncommon disease and its similarity to other diseases of the myocardium and endocardium. There is a two-layered structure of the myocardial wall consisting of a thin compacted epicardial layer and a thick non-compacted endocardial layer with prominent trabeculations and deep recesses

rationale for the use of high dose sustained release isosorbide 5 mononitrate in ischemic heart disease and chronic heart failure

Isosorbide-5-mononitrate is one of the two pharmacologically active metabolites of isosorbide dinitrate. At variance from its parent drug, it has a longer elimination half-life, no metabolic first-pass, and greater bioavailability, allowing once-daily administration as standard or as sustained-release formulations. Several trials have shown that isosorbide-5-mononitrate, in the form of sustained-released capsules administered once daily at doses ranging between 50 and 100 mg, is an effective symptomatic drug for the treatment of stable angina and chronic heart failure (CHF), and is now indicated for these conditions by American and European guide- lines. In particular, at 80 mg once-daily sustained-release isosorbide-5-mononitrate has been shown to have trough plasma levels below the minimum therapeutic concentration (100 ng/mL), ensuring a nitrate-free period as sufficient as to avoid nitrate tolerance. This 80 mg dosage is the only high dose sustained-release formulation of isosorbide-5-mononitrate currently marketed in Italy. Isosorbide-5-mononitrate also exerts positive hemodynamic effects (reduction in filling pressure and systemic vascular resistance, with increase in cardiac output) in heart failure in as- sociation with standard medical therapy and hydralazine, with a positive impact on patient prog- nosis. (Heart International 2007; 3: 98-111

Improved graft patency rates and mid-term outcome of diabetic patients undergoing total arterial myocardial revascularization

Objectives: Diabetes negatively affects the outcome of patients undergoing percutaneous transluminal coronary angioplasty (PTCA) or coronary surgery. However, data are lacking with respect to the impact of arterial revascularization in the diabetic population. Methods: Between 1999 and 2003, 100 of 491 diabetics underwent coronary artery bypass graft surgery (CABG) with total arterial grafting (Group 1, G1); these patients were compared with 100 diabetics undergoing conventional CABG with saphenous veins (Group 2, G2), who were matched for Euroscore and other risk factors such as age, obesity, hypertension, left ventricular ejection fraction (LVEF), previous myocardial infarction and chronic obstructive pulmonary disease (COPD). Results: Both groups had a similar number of diseased coronary vessels (G1=2.6 vs G2= 2.7) and received a similar degree of myocardial revascularization (grafted vessels: G1=2.2 vs G2=2.4). Early outcome was comparable between the groups in terms of ventilatory support (G1=10.8±6 vs G2=10.4±5 hours), intensive care unit (ICU) stay (G1=24±12 vs G2=25±14 hours) and major post-operative complications such as atrial fibrillation (G1=26% vs G2=28%), peri-operative myocardial infarction (G1=1% vs G2=2%)and prolonged ventilatory support (G1=6% vs G2=5%). Hospital mortality was 2% in G1 and 3% in G2. Angiography was performed at a mean follow-up of 34 months in 65.9% and 71.1% of hospital survivors of G1 and G2 respectively: patients of G1 showed a significantly higher patency rate (G1=96% vs G2=83.6%, p=0.02). Additionally, patients of G1 showed a significantly lower incidence of recurrent myocardial ischemia (G1=7 pts. vs G2=18 pts., p=0.03), late myocardial infarction (G1=2 pts. vs G2=10 pts., p=0.03) and need for coronary reintervention (G1=1 pt. vs G2=12 pts, p=0.004). Conclusions: Total arterial grafting in diabetic patients significantly improved the benefits of coronary surgery providing at mid term a higher graft patency rate with a lower incidence of cardiac related events. (Heart International 2006; 3-4: 136-40

A Prospective, Randomized, Double-Blind Comparison of the Long-Term Effects of Metoprolol Versus Carvedilol

Background—Both metoprolol and carvedilol produce hemodynamic and clinical benefits in patients with chronic heart failure; carvedilol exerts greater antiadrenergic effects than metoprolol, but it is unknown whether this pharmacological difference results in hemodynamic and clinical differences between the 2 drugs. Methods and Results—We randomized 150 patients with heart failure (left ventricular ejection fraction ≤0.35) to double-blind treatment with either metoprolol or carvedilol. When compared with metoprolol (124±55 mg/d), patients treated with carvedilol (49±18 mg/d) showed larger increases in left ventricular ejection fraction at rest (+10.9±11.0 versus +7.2±7.7 U, P=0.038) and in left ventricular stroke volume and stroke work during exercise (both P<0.05) after 13 to 15 months of treatment. In addition, carvedilol produced greater decreases in mean pulmonary artery pressure and pulmonary wedge pressure, both at rest and during exercise, than metoprolol (all P<0.05). In contrast, the metoprolol gr..

The study of left ventricular diastolic function by Doppler echocardiography: the essential for the clinician

An abnormal diastolic function of left ventricle represents the main pathophysiological mechanism responsible for different clinical states such as restrictive cardiomyopathy, infiltrative myocardial disease and, specially, diastolic heart failure (also called heart failure with preserved systolic function), which is present in a large number of patients with a clinical picture of pulmonary congestion