Semaglutide-eye-catching results

Semaglutide is a glucagon-like peptide-1 receptor agonist used either orally every day or subcutaneously once a week for the treatment of type 2 diabetes mellitus and,more recently,at higher doses,for the treatment of obesity.Both diseases are reaching epidemic proportions and often coexist,posing patients with a high risk for cardiovascular disease and death.Therefore,an agent such as semaglutide,which offers clinically significant weight loss and cardiovascular benefits,is essential and will be increasingly used in high-risk patients.However,during the SUSTAIN clinical trial program(Semaglutide Unabated Sustainability in treatment of type 2 diabetes),a safety issue concerning the progression and worsening of diabetic retinopathy emerged.The existing explanation so far mainly supports the role of the magnitude and speed of HbA1c reduction,a phenomenon also associated with insulin treatment and bariatric surgery.Whether and to which extent the effect is direct is still a matter of debate and an intriguing topic to investigate for suitable preventative and rehabilitative purposes.In this minireview,we will summarize the available data and suggest guidelines for a comprehensive semaglutide clinical utilization until new evidence becomes available.

Depression and chronic heart failure in the elderly： an intriguing relationship

Chronic heart failure and depressive disorders have a high prevalence and incidence in the elderly. Several studies have shown how depression tends to exacerbate coexisting chronic heart failure and its clinical outcomes and vice versa, especially in the elderly. The negative synergism between chronic heart failure and depression in the elderly may be approached only taking into account the multifaceted pathophysiological characteristics underlying both these conditions, such as behavioural factors, neurohormonal activation, inflammatory mediators, hypercoagulability and vascular damage. Nevertheless, the pathophysiological link between these two conditions is not well established yet. Despite the high prevalence of depression in chronic heart failure elderly patients and its negative prognostic value, it is often unrecognized especially because of shared symptoms. So the screening of mood disorders, using reliable questionnaires, is recommended in elderly patients with chronic heart failure, even if cannot substitute a diagnostic interview by mental health professionals. In this setting, treatment of depression requires a multidisciplinary approach including： psychotherapy, antidepressants, exercise training and electroconvulsive therapy. Pharmacological therapy with selective serotonin reuptake inhibitors, despite conflicting results, improves quality of life but does not guarantee better outcomes. Exercise training is effective in improving quality of life and prognosis but at the same time cardiac rehabilitation services are vastly underutilized.

Long-term metformin therapy and vitamin B12 deficiency: An association to bear in mind

To date,metformin remains the first-line oral glucose-lowering drug used for the treatment of type 2 diabetes thanks to its well-established long-term safety and efficacy profile.Indeed,metformin is the most widely used oral insulinsensitizing agent,being prescribed to more than 100 million people worldwide,including patients with prediabetes,insulin resistance,and polycystic ovary syndrome.However,over the last decades several observational studies and meta-analyses have reported a significant association between long-term metformin therapy and an increased prevalence of vitamin B12 deficiency.Of note,evidence suggests that long-term and high-dose metformin therapy impairs vitamin B12 status.Vitamin B12(also referred to as cobalamin)is a water-soluble vitamin that is mainly obtained from animal-sourced foods.At the cellular level,vitamin B12 acts as a cofactor for enzymes that play a critical role in DNA synthesis and neuroprotection.Thus,vitamin B12 deficiency can lead to a number of clinical consequences that include hematologic abnormalities(e.g.,megaloblastic anemia and formation of hypersegmented neutrophils),progressive axonal demyelination and peripheral neuropathy.Nevertheless,no definite guidelines are currently available for vitamin B12 deficiency screening in patients on metformin therapy,and vitamin B12 deficiency remains frequently unrecognized in such individuals.Therefore,in this“field of vision”article we propose a list of criteria for a cost-effective vitamin B12 deficiency screening in metformin-treated patients,which could serve as a practical guide for identifying individuals at high risk for this condition.Moreover,we discuss additional relevant topics related to this field,including:(1)The lack of consensus about the exact definition of vitamin B12 deficiency;(2)The definition of reliable biomarkers of vitamin B12 status;(3)Causes of vitamin B12 deficiency other than metformin therapy that should be identified promptly in metformin-treated patients for a proper differential diagnosis;and(4)Potential pathophysiological mechanisms underlying metformin-induced vitamin B12 deficiency.Finally,we briefly review basic concepts related to vitamin B12 supplementation for the treatment of vitamin B12 deficiency,particularly when this condition is induced by metformin.

Clinical significance of glycemic parameters on venous thromboembolism risk prediction in gastrointestinal cancer

To investigate the possible predictive role of routinely used glycemic parameters for a first venous thromboembolism (VTE) episode in gastrointestinal (GI) cancer ambulatory patients - with or without clinically diagnosed type 2 diabetes (T2D) or obesity - treated with chemotherapy.METHODSPre-treatment fasting blood glucose, insulin, glycated hemoglobin (HbA1c) and homeostasis model of risk assessment (HOMA) were retrospectively evaluated in a cohort study of 342 GI cancer patients. Surgery was performed in 142 (42%) patients with primary cancer, 30 (21%) and 112 (79%) of whom received neoadjuvant and adjuvant therapies, respectively. First-line chemotherapy was administered in 200 (58%) patients with metastatic disease. The study outcome was defined as the occurrence of a first symptomatic or asymptomatic VTE episode during active treatment.RESULTSImpaired glucose tolerance (IGT) or T2D were diagnosed in 30% of GI cancer patients, while overweight/obesity had an incidence of 41%. VTE occurred in 9.4% of patients (7% of non-diabetic non-obese), especially in those with a high ECOG score (P = 0.025). No significant association was found between VTE incidence and T2D, obesity, different tumor types, metastatic disease, Khorana class of risk, or different anti-cancer drugs, although VTE rates were substantially higher in patients receiving bevacizumab (17% vs 8%, P = 0.044). Conversely, all glucose metabolic indexes were associated with increased VTE risk at ROC analysis. Multivariate Cox proportional analyses confirmed that HOMA index (HR = 4.13, 95%CI: 1.63-10.5) or fasting blood glucose (HR = 3.56, 95%CI: 1.51-8.39) were independent predictors of VTE occurrence during chemotherapy.CONCLUSIONThe results here reported demonstrate that evaluating glucose metabolic asset may allow for VTE risk stratification in GI cancer, helping to identify chemotherapy-treated patients who might benefit from thromboprophylaxis. Further multicenter prospective studies involving a larger number of patients are presently needed.

Prognostic value of glycated hemoglobin in colorectal cancer

AIM To investigate the clinical significance of routinely used glycemic parameters in a cohort of colorectal cancer(CRC) patients.METHODS Pre-treatment fasting blood glucose, insulin, Hb A1 c and homeostasis model of risk assessment(HOMA-IR) were retrospectively evaluated in a case-control study of 224 CRC and 112 control subjects matched for sex, obesity and diabetes frequency and blood lipid profile.Furthermore, the prognostic value of routinely used glycemic parameters towards progression-free(PFS) and overall survival(OS) was prospectively evaluated.RESULTS Fasting blood glucose, insulin, HOMA-IR and HbA 1c(all P < 0.0001) levels were higher in non-diabetic CRC patients compared with obesity-matched controls. All parameters were associated with increased CRC risk at ROC analysis, but no relationship with clinical-pathological variables or survival outcomes was observed for glycemia, insulinemia or HOMA-IR. Conversely, advanced CRC stage(P = 0.018) was an independent predictor of increased Hb A1 c levels, which were also higher in patients who had disease progression compared with those who did not(P = 0.05). Elevated Hb A1 c levels showed a negative prognostic value both in terms of PFS(HR = 1.24) and OS(HR = 1.36) after adjustment for major confounders, which was further confirmed in a subgroup analysis performed after exclusion of diabetic patients.CONCLUSION HbA 1c might have a negative prognostic value in CRC, thus suggesting that glycemic metabolic markers should be carefully monitored in these patients, independently of overt diabetes.

The modulation of sirtuins and apoptotic proteins in rats after exhaustive exercise

A large body of evidence shows that a single bout of strenuous exercise induces oxidative stress in circu- lating human lymphocytes leading to lipid peroxide- tion, DNA damage, mitochondrial perturbations, and protein oxidation. In a training experiment, Wistar rats were divided into control group (CG) and exer- cise group (EG). After a running level exercise until exhaustion, we observed an increase in the mRNA content and protein expression of SIRT1 and SIRT7 in the EG compared to the CG. Moreover, such train- ing exercise did not change mRNA transcripts and protein expression of FOXO3A and GADD45. We also observed an increase of pro-apoptotic protein bax and a decrease of the anti-apoptotic protein bcl-2 in the EG. Accordingly, we observed a caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage only in EG rats. Statistical analysis of the data showed a significant correlation between SIRT1 and SIRT7 expression and apoptotic proteins such as bax, bcl-2 in both tissues. We conclude that, in both muscle, such exercise activates both a damaging apoptotic mecha- nism with bax increase and bcl-2 decrease and a counterbalancing protective mechanism with SIRT1 and SIRT7 increase.

Bisphosphonates and adipogenesis: Evidence for alendronate inhibition of adipocyte differentiation in 3T3-L1 preadipocytes through a vitamin D receptor mediated effect

Background: Adipocyte and osteoblast derive from the same mesenchimal progenitor. Age-related decrease in bone mass is accompanied by an increase in marrow adipose tissue. Vitamin D3 (VD3) inhibits adipogenesis in 3T3-L1 preadipocytes. Recently it has been demonstrated that alendronate (ALN) inhibits adipogenesis while promoting osteoblast differentiation of mesenchimal stem cells. Aim of the Study: To evaluate the role of ALN on adipocyte differentiation in vitro and the potential synergic role of VD3 co-treatment. Procedures: Murine 3T3-L1 and 3T3-F442A preadipocytes were routinely differentiated in presence of ALN and VD3 10-9 - 10-7 M for 7 days and then stained with Oil Red O. The effect of these treatments on mRNA expression of the main molecular markers of adipocyte differentiation (PPARγ and C/EBPα) and VD Receptor (VDR) were analyzed through RT-PCR. Results: Both ALN and VD3 showed a marked anti-adipogenic effect on 3T3-L1 cells. Co-incubation of ALN 10-8 M and VD3 10-9 M displayed no synergic effect on inhibition of adipogenesis. PPARγ mRNA expression was significantly reduced by ALN and VD3. mRNA expression of C/EBPα was reduced only by VD3 treatment. An increase in VDR mRNA expression of 3T3-L1 cells was observed with both ALN and VD3. On the contrary, 3T3-F442A cells, which are in a more advanced adipogenic differentiation stage compared to 3T3-L1, did not express detectable levels of VDR. Interestingly, adipose differentiation of 3T3-F442A was not affected by ALN nor VD3. These results suggest that VDR may represent the molecular target of the anti-adipogenic effect of ALN. Conclusion: VDR plays a critical role in mediating the anti-adipogenic effect of ALN. Further studies to clarify this mechanism are warranted.

Characterization of the Ear Canal Bacterial Flora Present in Hearing Aids (HA) Wearing Subjects

The use of hearing aids (HA) is considered a predisposing factor for ear microbial infections. We undertook this study to compare the presence and nature of the microbial flora inhabiting of ears of HA and non-HA (nHA) users. Swab samples of the ears of HA and nHA users were collected from the Institute of Otolaryngology, “Cattolica del Sacro Cuore” University “Agostino Gemelli”, Rome, Italy. Swab samples were taken from the ear canal of 57 HA and 33 nHA users. The components of the microbial flora present on each swab sample were identified and characterized at the level of species. A total of 41 different bacterial species were identified. A statistically significant prevalence of polymicrobial communities was found in ears presenting signs of inflammation (2.5 ± 1.7 vs 2.1 ± 1.3;P = 0.02) and in HA users (2.3 ± 1.2 vs 1.7 ± 1.0;P = 0.002). Few putative pathogens were detected. Candida albicans spp. was not isolated in our study. A small number of swab samples presented no microbial growth. Bacterial species isolated from HA users with and without inflammation were assayed for the ability to form biofilm. Among gram-positive and gram-negative bacteria, S. aureus, CoNS, P. aeruginosa and K. pneumoniae were found to be strong biofilm producers. S. aureus and P. aeruginosa, isolated only from the ears of HA and nHA users presenting signs of inflammation, were further analyzed for their antibiotic-resistance profile and characterized by the Multilocus Sequence Typing (MLST) assay. The highest rates of antibacterial resistance were in S. aureus to penicillin (75.5%) and in P. aeruginosa, to amoxicillin-clavulanic acid, cefotaxime, ertapenem, tigecycline and trime-thoprim-sulfamethoxazole (100%). Moreover, three S. aureus strains (37.5%) were methicillin-resistant (MRSA). Of the eight S. aureus isolates, we identified six sequence types (ST) indicating that 75% are likely independent clones. For what it concerned P. aeruginosa, six different STs were assigned. Interestingly, two out of the six strains presented newly identified ST values. This study sheds new light on the combined effect of the presence of HA devices and signs of external ear inflammation on the composition of the ear bacterial flora. Our results reinforce the need to practice careful hygiene of HA devices to prevent serious ear canal infections.