Liraglutide Improves Cardiovascular Risk as an Add-on to Metformin and Not to Insulin Secretagogues in Type 2 Diabetic Patients: A Real-life 48-Month Retrospective Study.

INTRODUCTION: Although liraglutide is widely recognized to have glycemic and extra-glycemic effects, few studies have compared these effects in relation to hypoglycemic treatment starting from the diagnosis of diabetes. We evaluated the effectiveness of liraglutide in reducing the Framingham risk score (FRS) and visceral adiposity index (VAI) in relation to first-line hypoglycemic treatment from diagnosis of type 2 diabetes, continued without any changes. METHODS: We selected 105 diabetic outpatients who were treated with liraglutide for at least 48 months as an add-on therapy to metformin alone (group A, n = 52) or insulin secretagogues (group B, n = 53) from diagnosis time. RESULTS: Although both groups showed a reduction in BMI, waist circumference, blood pressure, HbA1c and triglycerides, only group A showed a significant reduction in FRS (p < 0.001) and VAI (p = 0.012) after 48 months. No significant intergroup difference was found for any parameters at either baseline or 48 months, with the exception of FRS at 48 months, lower in group A (p = 0.002), regardless of duration of disease, improvement in glycemic control and VAI. CONCLUSION: Our data show that during a 48-month follow-up liraglutide was more efficacious in reducing cardiovascular risk than when it was used as add-on therapy to the first-line therapy from diagnosis with metformin and not with insulin secretagogues

Correlation between adrenal function, growth hormone secretion, and insulin sensitivity in children with idiopathic growth hormone deficiency

Purpose Patients with growth hormone deficiency (GHD) demonstrate an increased cortisol/cortisone ratio which could potentially explain the metabolic features of GHD, while GH treatment (GHT) could increase the cortisol metabolism. Methods In 35 children (27 M, mean age 10.1 years) with idiopathic GHD at baseline and after 12 months of GHT and in 25 controls, in addition to metabolic parameters, we assessed adrenal function by morning serum cortisol, its peak, and its area under the curve (AUCCOR) during insulin tolerance test (ITT). Results A cortisol peak <18 \ub5g/dl was shown in 22 and 31% of GHD children at baseline and after GHT, respectively. At baseline, GHD children had lower fasting glucose (p < 0.001) and ISI-Matsuda (p = 0.042), with concomitant higher Homa-IR (p = 0.006) and morning cortisol (p = 0.012) than controls. Morning cortisol was negatively correlated with GH (p < 0.001), fasting glucose (p < 0.001) and ISI-Matsuda (p < 0.001) and positively with Homa-IR (p = 0.010). Both cortisol peak and AUCCOR were negatively correlated with GH (all p < 0.001) and ISI-Matsuda (p = 0.016 and p = 0.001, respectively). After 12 months of GHT, a significant increase in fasting glucose (p < 0.001), and Homa-IR (p = 0.011) was documented, with a concomitant decrease in morning cortisol (p = 0.002), AUCCOR (p = 0.038), total (p = 0.003) and LDL-cholesterol (p = 0.016). No significant correlations were found among cortisol levels and all parameters were investigated. Conclusions Cortisol levels correlate with GH secretion and with many metabolic parameters in GHD children, while the metabolic effects during GHT are mainly due to GHT per se and less to cortisol reduction

Reflux and dyspeptic symptom patterns in patients with non erosive reflux disease (NERD) subclassified using 24-hour ambulatory intraluminal pH-Impedance

Ample evidence supports that prostate tumor metastasis originates from a rare population of cancer cells, known as cancer stem cells (CSCs). Unfortunately, little is known about the identity of these cells, making it difficult to target the metastatic prostate tumor. Here, for the first time, we report the identification of a rare population of prostate cancer cells that express the Tie-2 protein. We found that this Tie-2High population exists mainly in prostate cancer cell lines that are capable of metastasizing to the bone. These cells not only express a higher level of CSC markers but also demonstrate enhanced resistance to the chemotherapeutic drug Cabazitaxel. In addition, knockdown of the expression of the Tie-2 ligand angiopoietin (Ang-1) led to suppression of CSC markers, suggesting that the Ang-1/Tie-2 signaling pathway functions as an autocrine loop for the maintenance of prostate CSCs. More importantly, we found that Tie-2High prostate cancer cells are more adhesive than the Tie-2Low population to both osteoblasts and endothelial cells. Moreover, only the Tie-2High, but not the Tie-2Low cells developed tumor metastasis in vivo when injected at a low number. Taken together, our data suggest that Tie-2 may play an important role during the development of prostate tumor metastasis

Clinical implications of discordant early molecular responses in CML patients treated with imatinib

A reduction in BCR-ABL1/ABL1IS transcript levels to &lt;10% after 3 months or &lt;1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple BCR-ABL1 thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant BCR-ABL1/ABL1IS transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (≥ MR4; 71.5% vs. 16.1%) compared to individuals with BCR-ABL1/ABL1IS levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3-and 6-month time points. Among these patients, those with BCR-ABL1/ABL1IS values &gt;10% at 3 months but &lt;1% at 6 months fared significantly better than individuals with BCR-ABL1/ABL1IS &lt;10% at 3 months but &gt;1% at 6 months (event-free survival 68.2% vs. 32.7%; p &lt; 0.001). Likewise, subjects with BCR-ABL1/ABL1IS at 3 months &gt;10% but &lt;1% at 6 months showed a higher cumulative incidence of MR4 compared to patients with BCR-ABL1/ABL1IS &lt;10% at 3 months but &gt;1% at 6 months (75% vs. 18.2%; p &lt; 0.001). Finally, lower BCR-ABL1/GUSIS transcripts at diagnosis were associated with BCR-ABL1/ABL1IS values &lt;1% at 6 months (p &lt; 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points

BCR-ABL1 doubling-times and halving-times may predict CML response to tyrosine kinase inhibitors

In Chronic Myeloid Leukemia (CML), successful treatment requires accurate molecular monitoring to evaluate disease response and provide timely interventions for patients failing to achieve the desired outcomes. We wanted to determine whether measuring BCR-ABL1 mRNA doubling-times (DTs) could distinguish inconsequential rises in the oncogene’s expression from resistance to tyrosine kinase inhibitors (TKIs). Thus, we retrospectively examined BCR-ABL1 evolution in 305 chronic-phase CML patients receiving imatinib mesylate (IM) as a first line treatment. Patients were subdivided in two groups: those with a confirmed rise in BCR-ABL1 transcripts without MR3.0 loss and those failing IM. We found that the DTs of the former patients were significantly longer than those of patients developing IM resistance (57.80 vs. 41.45 days, p = 0.0114). Interestingly, the DT values of individuals failing second-generation (2G) TKIs after developing IM resistance were considerably shorter than those observed at the time of IM failure (27.20 vs. 41.45 days; p = 0.0035). We next wanted to establish if decreases in BCR-ABL1 transcripts would identify subjects likely to obtain deep molecular responses. We therefore analyzed the BCR-ABL1 halving-times (HTs) of a different cohort comprising 174 individuals receiving IM in first line and observed that, regardless of the time point selected for our analyses (6, 12, or 18 months), HTs were significantly shorter in subjects achieving superior molecular responses (p = 0.002 at 6 months; p &lt; 0.001 at 12 months; p = 0.0099 at 18 months). Moreover, 50 patients receiving 2G TKIs as first line therapy and obtaining an MR3.0 (after 6 months; p = 0.003) or an MR4.0 (after 12 months; p = 0.019) displayed significantly shorter HTs than individuals lacking these molecular responses. Our findings suggest that BCR-ABL1 DTs and HTs are reliable tools to, respectively, identify subjects in MR3.0 that are failing their assigned TKI or to recognize patients likely to achieve deep molecular responses that should be considered for treatment discontinuation

One Year of Dapaglifozin Add-On Therapy Ameliorates Surrogate Indexes of Insulin Resistance and Adiposity in Patients with Type 2 Diabetes Mellitus

Introduction: This study investigates the effects of dapagliflozin on the visceral adiposity index (VAI), lipid accumulation product (LAP), product of triglycerides and glucose (TyG) and triglycerides to HDL-cholesterol ratio (TG/HDL-C) in patients with type 2 diabetes mellitus (T2D). Methods: In this real-life study, dapaglifozin was added to metformin alone (group 1, no. 42) or insulin plus metformin (group 2, no. 58) in 100 T2D patients. Results: In group 1, after 6 months of dapaglifozin addition, a significant decrease in BMI (p &lt; 0.001), waist circumference (WC) (p &lt; 0.001), systolic blood pressure (SBP) (p = 0.009), diastolic blood pressure (DBP) (p = 0.012), mean fasting blood glucose (FBG), post-breakfast glucose (PBG), post-lunch glucose (PLG) and post-dinner glucose (PDG) (all p &lt; 0.001), HbA1c (p &lt; 0.001), VAI (p = 0.020), LAP (p = 0.028), Tyg (p &lt; 0.001), TG/HDL-C (p = 0.020) and glutamate pyruvate transaminase (GPT) (p &lt; 0.001) was observed compared to baseline. After 12 months a significant decrease in BMI (p &lt; 0.001), WC (p = 0.006), SBP (p = 0.023), DBP (p = 0.005), mean FPG, PBG, PLG and PDG (all p &lt; 0.001), HbA1c (p &lt; 0.001), total cholesterol (p = 0.038), triglycerides (p = 0.026), VAI (p = 0.013), GPT (p &lt; 0.001), LAP index (p = 0.024), Tyg index (p &lt; 0.001) and TG/HDL-c ratio (p = 0.016) was observed compared to baseline. In group 2, after 6 months of dapaglifozin addition, a significant decrease in BMI (p &lt; 0.001), WC (p &lt; 0.001), SBP (p = 0.015), DBP (p = 0.007), mean FPG, PBG, PLG and PDG (all p &lt; 0.001), HbA1c (p &lt; 0.001), VAI (p = 0.040), LAP (p = 0.047), Tyg (p &lt; 0.001), TG/HDL-C (p = 0.048) and GPT (p &lt; 0.001) was observed compared to baseline. By contrast, after 12 months a significant decrease in BMI (p &lt; 0.001), WC (p &lt; 0.001), SBP (p = 0.001), DBP (p = 0.002), mean FPG, PBG, PLG and PDG (all p &lt; 0.001), HbA1c (p &lt; 0.001), GPT (p &lt; 0.001) and Tyg index (p = 0.003) was observed compared to baseline. Conclusions: Dapagliflozin treatment significantly reduced surrogate indexes of insulin resistance and adiposity in patients with T2D

Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin

Aims/hypothesis Several publications suggest an association between certain types of insulin and cancer, but with conflicting results. We investigated whether insulin glargine (A21Gly,B31Arg,B32Arg human insulin) is associated with an increased risk of cancer in a large population-based cohort study. Methods Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. In a cohort of incident users of insulin, the association between insulin glargine and other insulin analogues, respectively, and cancer was analysed in comparison with human insulin using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. The first hospital admission with a primary diagnosis of cancer was considered as the main outcome; secondary analyses were performed with specific cancers as outcomes. Results Of the 19,337 incident insulin users enrolled, 878 developed cancer. Use of insulin glargine was associated with a lower risk of malignancies in general in comparison with human insulin (HR 0.75, 95% CI 0.71, 0.80). In contrast, an increased risk was found for breast cancer (HR 1.58, 95% CI 1.22, 2.05). Dose-response relationships could not be identified. Conclusion/interpretation Users of insulin glargine and users of other insulin analogues had a lower risk of cancer in general than those using human insulin. Both associations might be a consequence of residual confounding, lack of adherence or competing risk. However, as in previous studies, we demonstrated an increased risk of breast cancer in users of insulin glargine in comparison with users of human insulin

New understandings of the genetic basis of isolated idiopathic central hypogonadism

Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and is fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome (KS). KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH (nICH), justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network