Suitability and Usefulness of a Flexible Dosing Timing of Oral Semaglutide to Maximize Benefit in Clinical Practice: An Expert Panel.

From clinical trials and observational data, oral semaglutide has proven to be the most effective second-line oral therapy for the management of patients with type 2 diabetes. This review aims to describe the perspective of an Italian expert panel that addressed the potential challenges arising during the use of oral semaglutide in the free-living conditions of routine clinical care. A group of Italian experts discussed and generated insights into the use of oral semaglutide in clinical practice. Key topics included the effectiveness of oral semaglutide in clinical practice, the positioning of the agent to optimize the treatment benefits, the possibility to adopt flexibility in the administration schedule, critical issues encountered, the role of patient communication and information in the importance of dose escalation and management of adverse events. Available data on efficacy and effectiveness of oral semaglutide from randomized clinical trials and real-world studies were reported, along with factors that determine tolerability and persistence on treatment. The debate over a fixed versus a flexible dosing schedule was critically addressed, providing anecdotical clues from a small case series and a real-world database. Additionally, a set of recommendations for clinicians to consider when prescribing oral semaglutide and during the process of patient monitoring were provided.

Bone Disruption and Environmental Pollutants.

BACKGROUND: Endocrine Disrupting Chemicals (EDCs) are ubiquitous and may significantly contribute to environmental pollution and contamination in humans and wildlife. Ecological pollutants could interfere with bone homeostasis through different mechanisms, including hormonal imbalance, direct osteoblast toxicity, and enhancement of osteoclasts activity, leading to either osteopenia or osteoporosis. Among these chemicals, bisphenols, dioxins, polycyclic aromatic hydrocarbons, polychlorobiphenyls, poly- and perfluoroalkyl, phthalates, parabens, organotins, and cadmium may play a role in the bone disruption. METHODS: Authors searched PubMed/MEDLINE, ISI-web of knowledge, and Google scholar databases for medical subject headings terms and free-text words related to the classes mentioned above of chemicals and bone metabolism and remodeling for better clarifying and understanding the main mechanisms of bone disruption. RESULTS: Several EDCs act as xeno-estrogens. Considering that estrogens play a significant role in regulating bone remodeling, most of these chemicals generate hormonal imbalance with possible detrimental consequences on bone tissue structure and its mechanical and non-mechanical properties. DISCUSSION: Much evidence about bone disruptors was obtained from in vitro studies or animal models with equivocal results. Besides, a few data have been acquired from humans, and most of these data focused on the impact of EDCs on bone mineral density without considering their influence on long-term fracture risk. Moreover, humans may be exposed to a mixture of EDCs, and the final effect on bone metabolism might be attributable to either synergistic or antagonist effects. Age of first exposure, cumulative exposure over time, and the usually observed non-monotonic dose-response curve for EDCs should be considered as other essential variables influencing bone metabolism's final effect. CONCLUSION: Given these variables, observational studies are needed to analyze this issue for ecological purposes better and preserve bone health.

Glifozines and cardiorenal outcomes.

Diabetes mellitus, with its complications, is one of the major health problems in economically developed countries and its prevalence is constantly increasing. Kidneys and heart involvement represent main comorbidities in diabetic patients often leading to organ failure. The treatments available until a few years ago are often associated with hypoglycemia, weight gain, gastro-intestinal disorders and other side effects together with serious adverse effects on renal function. The new frontiers of diabetic cardionephropathy treatment are mainly focused on delay of heart and renal failure both on diabetic and nondiabetic patients ad it was shown by last data reports. In the following review, we will focus on Gliflozins, one of the newest classes of hypoglycemic drugs that have shown to hold peculiar pharmacological properties in managing cardiac and renal complications.

Rac1 Modulates Endothelial Function and Platelet Aggregation in Diabetes Mellitus.

BACKGROUND: Vascular complications and abnormal platelet function contribute to morbidity and mortality in diabetes mellitus. We hypothesized that the Rho-related GTPase protein, Rac1, can influence both endothelial and platelet function and might represent a potential novel therapeutic target in diabetes mellitus. METHODS AND RESULTS: We used both in vitro and ex vivo approaches to test the effects of pharmacological inhibition of Rac1 during hyperglycemic condition. We evaluated the effect of NSC23766, a pharmacological inhibitor of Rac1, on vascular function in diabetic mice and platelet aggregation in diabetic subjects. We demonstrated that the administration of NSC23766 protects from hyperglycemia-induced endothelial dysfunction, restoring NO levels, and reduces oxidative stress generated by nicotinamide adenine dinucleotide phosphate oxidase. Mechanistically, we identified Rho-associated coiled-coil serine/threonine kinase-1 as a downstream target of Rac1. Moreover, we reported that during hyperglycemic conditions, human platelets showed hyperactivation of Rac1 and impaired NO release, which were both partially restored after NSC23766 treatment. Finally, we characterized the antiplatelet effect of NSC23766 during hyperglycemic conditions, demonstrating the additional role of Rac1 inhibition in reducing platelet aggregation in diabetic patients treated with common antiplatelet drugs. CONCLUSIONS: Our data suggest that the pharmacological inhibition of Rac1 could represent a novel therapeutic strategy to reduce endothelial dysfunction and platelet hyperaggregation in diabetes mellitus.