Aim: To determine whether the magnitude of the cardiorenal benefits of sodiumglucose co-transporter-2 inhibitors (SGLT2is) varies with baseline kidney function. Methods:We searched randomized, placebo-controlled trials testing the effects of SGLT2is on renal and cardiovascular outcomes. Efficacy outcomes, stratified by baseline estimated glomerular filtration rate (eGFR) categories, included renal disease progression, a composite heart failure (HF) outcome and mortality.Results: Thirteen trials testing SGLT2is in 90 402 participants with available eGFR data were included. The risk of bias was judged as low for all trials. SGLT2is reduced the relative risks of renal disease progression by 27% to 57% and of HF outcomes by 13% to 32% across different eGFR categories, with an overall low heterogeneity. Meta-regression analyses showed a significant direct relationship between baseline eGFR and the magnitude of SGLT2is' renal protection (P = .003). The greatest risk reduction was in participants with an eGFR of 90 ml/min/1.73m 2 or higher (HR 0.43, 95% CI: 0.32-0.58) and the smallest was in those with an eGFR of less than 30 ml/min/1.73m 2 (HR 0.73, 95% CI: 0.62-0.86, P < .001). Conversely, for HF, the greatest risk reduction was in those with an eGFR of less than 30 ml/min/1.73m 2 (HR 0.68, 95% CI: 0.48-0.96) and the smallest was in those with an eGFR of 90 ml/min/1.73m 2 or higher (HR 0.87, 95% CI: 0.56-1.34).Conclusions: SGLT2is reduce the risk of renal and HF outcomes for all eGFR categories. The greatest benefits in terms of kidney protection may be achieved by early initiation of SGLT2is in people with preserved eGFR. The greatest risk reduction for HF outcomes is observed in people with lower eGFR values.Ernesto Maddaloni and Ilaria Cavallari contributed equally to this article.

Atherosclerosis is the leading cause of death worldwide, especially in patients with type 2 diabetes mellitus (T2D). GLP-1 receptor agonists and DPP-4 inhibitors were demonstrated to play a markedly protective role for the cardiovascular system beyond their glycemic control. Several cardiovascular outcome trials (CVOT) reported the association between using these agents and a significant reduction in cardiovascular events in patients with T2D and a high cardiovascular risk profile. Moreover, recent evidence highlights a favorable benefit/risk profile in myocardial infarction and percutaneous coronary revascularization settings. These clinical effects result from their actions on multiple molecular mechanisms involving the immune system, platelets, and endothelial and vascular smooth muscle cells. This comprehensive review specifically concentrates on these cellular and molecular processes mediating the cardiovascular effects of incretins-like molecules, aiming to improve clinicians’ knowledge and stimulate a more extensive use of these drugs in clinical practice as helpful cardiovascular preventive strategies.

The clinical evidence on the efficacy of lipid lowering therapy in patients with coronary artery disease (CAD) is unequivocally established. However, the effects of these therapies on plaque composition and stability are less clear. The use of intracoronary imaging (ICI) technologies has emerged as a complement to conventional angiography to further characterize plaque morphology and detect high-risk plaque features related to cardiovascular events. Along with clinical outcomes studies, parallel imaging trials employing serial evaluations with intravascular ultrasound (IVUS) have shown that pharmacological treatment has the capacity to either slow disease progression or promote plaque regression, depending on the degree of lipid lowering achieved. Subsequently, the introduction of high-intensity lipid lowering therapy led to much lower levels of low-density lipoprotein cholesterol (LDL-C) levels than achieved in the past, resulting in greater clinical benefit. However, the degree of atheroma regression showed in concomitant imaging trials appeared more modest as compared to the magnitude of clinical benefit accrued from high-intensity statin therapy. Recently, new randomized trials have investigated the additional effects of achieving very low levels of LDL-C on high-risk plaque features—such as fibrous cap thickness and large lipid accumulation—beyond its size. This paper provides an overview of the currently available evidence of the effects of moderate to high-intensity lipid lowering therapy on high-risk plaque features as assessed by different ICI modalities, reviews data supporting the use of these trials, and analyse the future perspectives in this field.

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A 55-years-old male affected by heart failure with reduced ejection fraction (HFrEF) was accepted into the Cardiology Department for increasing dyspnea during the last few months. He previously underwent implantation of a biventricular implantable cardioverter defibrillator (ICD) in primary prevention. Medical history included healthy coronary vessels at invasive coronary angiography and an episode of transient ischemic attack (TIA). The patient was referred to our center to evaluate the dyspnea components and to establish an etiology for the novel onset of left ventricular impairment. He underwent a left-right catheterization that did confirm the absence of obstructive coronary disease and signs of pulmonary hypertension (PH) at rest. The transthoracic echocardiogram showed a dilated left ventricle and global hypokinesia (LVEF of 35%). During the stay, the therapy was further optimized according to the latest European guidelines. Before discharge, in order to better assess the dyspnea and the limited tolerance to exercise, a cardiopulmonary exercise testing (CPET) was performed. CPET showed that the VO2 peak was severely reduced compared to the predicted value (16.8 ml/kg/min, corresponding to 51% of the predicted). After 6 minutes of exercise, at around 60 WR, a considerable increase in PETO2 and RER with a concomitant decrease in PETCO2 and a slight oxygen desaturation were observed. Also, a deep increase in VE/VCO2 slope was seen, underlying an exercise-induced pulmonary hypertension. In the suspicion of an inter-atrial shunt, a subsequent rest transthoracic echocardiogram with a bubble test was performed, demonstrating the presence of a patent foramen ovale (PFO). Discussion The foramen ovale is a vestigial communication between the atria that works as a bypass of the pulmonary circulation during fetal life and then seals at birth after the start of breathing in most people. In around 25% of adults, patency of foramen ovale persists and, in some cases, can lead to a source of a right-to-left shunt, particularly in patients with heart failure that can experience PH at rest or during exercise. This may allow a mixture of oxygenated and non-oxygenated blood that affects pulmonary gas exchange efficiency and may allow blood clots formed in the right circulation to embolize into the left circulation. From a pathophysiological point of view, a right-to-left passage of deoxygenated blood induces the activation of chemoreceptors which induce hyperventilation to adequately compensate for the high amount of CO2 in blood from the right sections of the heart. In people not experiencing pulmonary pressure increase during exercise, right-to-left shunt via a PFO is very unlikely since left atrial pressure is higher than right atrial pressure. However, in the presence of PH, right atrial pressure can overcome left atrial pressure and force venous blood through the defect directly into the systemic circulation. The concomitant increase in VE/VCO2 slope underlines exercise-induced PH, which is frequently associated with heart failure and further contributes to exercise intolerance. Conclusions In the presented case, CPET helped diagnose a misunderstood PFO with a right-to-left shunt induced by effort in a patient with a previous TIA. This observation demonstrates that it could be helpful to identify this eventuality during exercise, to discern patients with higher risk of cardiovascular events who would benefit from a percutaneous closure.