Aims : Glucose-lowering, glucagon-like peptide-1 (GLP-1) receptor agonists reduce incidence of major cardiovascular (CV) events in patients with Type 2 diabetes mellitus (DM). However, randomized clinical trials reported inconsistent effects on myocardial infarction (MI) and stroke, and limited data in DM patients without established CV disease (CVD). Very recently, new relevant evidence was available from additional CV outcome trials (CVOTs) that also included large subgroups of patients with DM without established CVD. Thus, the aim of this meta-analysis was to investigate the effects of GLP-1 receptor agonists on major CV events and safety in DM patients with and without established CVD. Methods and results : In this trial-level meta-analysis, we analysed data from randomized placebo-controlled CVOTs assessing efficacy and safety of GLP-1 receptor agonists in adult patients with Type 2 DM. We searched PubMed, Embase, Cochrane, ISI Web of Science, SCOPUS, and clinicaltrial.gov databases for eligible trials. Of 360 articles identified and screened for eligibility, seven CVOTs were included, with an overall of 56 004 patients included. The difference in efficacy with respect to the major adverse cardiovascular events (MACE) primary endpoint (including CV mortality, non-fatal MI, and non-fatal stroke) between patients with established CVD and patients with CV risk factors only was not significant [pooled interaction effect, expressed as ratio of hazard ratio (HR) 1.06, 95% confidence interval (CI) 0.85–1.34]. In the analysis of the whole population of DM patients, GLP-1 receptor agonists showed a significant 12% reduction in the hazard of the three-point MACE composite endpoint (HR 0.88, 95% CI 0.80–0.96) and a significant reduction in the risk of CV mortality (HR 0.88, 95% CI 0.79–0.98), all-cause mortality (HR 0.89, 95% CI 0.81–0.97), fatal and non-fatal stroke (HR 0.84, 95% CI 0.76–0.94), and heart failure (HF) hospitalization (HR 0.92, 95% CI 0.86–0.97). No significant effect was observed for fatal and non-fatal MI (HR 0.91, 95% CI 0.82–1.02), although in a sensitivity analysis, based on a less conservative statistical approach, the pooled HR become statistically significant (HR 0.91, 95% CI 0.83–1.00; P = 0.039). No excess of hypoglycaemia, pancreatitis, and pancreatic cancer was observed between GLP-1 receptor agonists and placebo. Conclusion : Glucagon-like peptide-1 receptor agonists significantly reduce MACE, CV and total mortality stroke, and hospitalization for HF, with a trend for reduction of MI, in patients with Type 2 DM with and without established CVD.

Many efforts to reduce prostate specific antigen (PSA) overdiagnosis and overtreatment have been made. To this aim, Prostate Health Index (Phi) and Prostate Cancer Antigen 3 (PCA3) have been proposed as new more specific biomarkers. We evaluated the ability of phi and PCA3 to identify prostate cancer (PCa) at initial prostate biopsy in men with total PSA range of 2–10 ng/ml. The performance of phi and PCA3 were evaluated in 300 patients undergoing first prostate biopsy. ROC curve analyses tested the accuracy (AUC) of phi and PCA3 in predicting PCa. Decision curve analyses (DCA) were used to compare the clinical benefit of the two biomarkers. We found that the AUC value of phi (0.77) was comparable to those of %p2PSA (0.76) and PCA3 (0.73) with no significant differences in pairwise comparison (%p2PSA vs phi p = 0.673, %p2PSA vs. PCA3 p = 0.417 and phi vs. PCA3 p = 0.247). These three biomarkers significantly outperformed fPSA (AUC = 0.60), % fPSA (AUC = 0.62) and p2PSA (AUC = 0.63). At DCA, phi and PCA3 exhibited a very close net benefit profile until the threshold probability of 25%, then phi index showed higher net benefit than PCA3. Multivariable analysis showed that the addition of phi and PCA3 to the base multivariable model (age, PSA, %fPSA, DRE, prostate volume) increased predictive accuracy, whereas no model improved single biomarker performance. Finally we showed that subjects with active surveillance (AS) compatible cancer had significantly lower phi and PCA3 values (p<0.001 and p = 0.01, respectively). In conclusion, both phi and PCA3 comparably increase the accuracy in predicting the presence of PCa in total PSA range 2–10 ng/ml at initial biopsy, outperforming currently used %fPSA.

Objective The treatment of children with subclinical hypothyroidism (SH) is controversial for TSH values between 4.5 and 10 mU/l. The aim of this cross-sectional, controlled study was to evaluate growth and intellectual outcome in children with persistent SH who have never been treated with levothyroxine. Design and methods Clinical and auxological parameters, thyroid function, and intellectual outcome were evaluated in 36 children with persistent SH at the age of 9.7±0.6 (range 4–18.0) years. Children had been followed longitudinally for 3.3±0.3 (range 2.0–9.3) years, from first diagnosis of SH until enrollment in the study. Thirty-six age- and sex-matched children were enrolled in the study as controls. Results At study entry, height (−0.8±0.2 SDS), bone age/chronological age (BA/CA ratio 0.92±0.6), and body mass index (BMI −0.1±0.2 SDS) in SH children were normal. Despite long-term duration of SH, none of these parameters showed a worsening with respect to height (−0.7±0.2 SDS), BA/CA (0.97±0.03), and BMI (−0.1±0.2) at the time of first SH detection. None of the children showed overt signs or symptoms of hypothyroidism during the follow-up. Verbal (99.1±2.2), performance (100.4±1.9), and full-scale (99.7±1.9) intelligence quotient (IQ) scores in SH children were normal and comparable to those of controls. No relationship was detected between IQ scores and the degree or duration of SH. Conclusions Persistent SH in children is not associated with alterations in growth, bone maturation, BMI, and cognitive function or other complaints that could be ascribed to SH even after several years without therapeutic intervention.