Effect of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on glycemia, body weight, and new-onset diabetes mellitus

Statin therapy modestly increases new-onset diabetes risk. The effect of proprotein convertase subtilisin/kexin type 9 inhibition on new-onset diabetes, glycemia, and weight remains unclear. We studied the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on fasting plasma glucose, glycated hemoglobin, weight, and new-onset diabetes mellitus. We pooled 1-year (48-week) data for participants who had completed an evolocumab parent study before entering an open-label extension (OLE) trial. Data were available for 4,802 participants (1,602 on standard of care [SOC]; 3,200 on evolocumab plus SOC) in 2 OLE trials. Evolocumab lowered low-density lipoprotein cholesterol by approximately 60% compared with SOC alone. Over the first year of the OLE trials, there was no difference in median (Q1, Q3) change in glycated hemoglobin (0.1% [-0.1, 0.2] for both SOC and evolocumab plus SOC) and fasting plasma glucose (0.06 mmol/L [-0.28, 0.38 mmol/L] for SOC and 0.06 mmol/L [-0.28, 0.44 mmol/L] for evolocumab plus SOC). Mean weight change (standard error) at 1 year was -0.1 kg (0.2) on SOC compared with 0.3 kg (0.1) on evolocumab plus SOC. The exposure-adjusted incidence rate (95% confidence intervals) for new-onset diabetes per 100 patient years was 3.7 (2.9 to 4.7) on control/SOC alone and 3.9 (3.2 to 4.6) on evolocumab/evolocumab plus SOC treatment. Glycemic changes observed in 6,430 participants at week 12 in the parent studies were comparable with OLE trial findings. In conclusion, evolocumab therapy has no effect on glucose homeostasis over 1 year of open-label treatment

Polymorphisms in the GTP cyclohydrolase gene (GCH1) are associated with ratings of capsaicin pain

In this paper, the results obtained on the perspectives of older adults are presented, particularly in relation to their present situation and future projection. 85 older adults (65 women and 20 men) who took part in different institutions of La Plata City were included. The reflection workshops were in general about aging, psychological and social changes and considerations on the time dimension that they bring. Implementing these workshops about the mentioned themes has allowed us to establish some issues of interest to develop, design and carry out a specific process of guidance for older adults, in which the protagonist is the subject with its desires and interests, as we conceive that in guidance it is essential to consider the singularity, to support them during the aging process (in some cases marked by retirement), so the older adults can question themselves about their new possibilities, can decide where to be involved, question themselves about interests, motivations and desires, often postponed, since it is not about spend the spare time, but to make new projects and achieve them. &nbsp

Growth hormone is permissive for neoplastic colon growth

Growth hormone (GH) excess in acromegaly is associated with increased precancerous colon polyps and soft tissue adenomas, whereas short-stature humans harboring an inactivating GH receptor mutation do not develop cancer. We show that locally expressed colon GH is abundant in conditions predisposing to colon cancer and in colon adenocarcinoma-associated stromal fibroblasts. Administration of a GH receptor (GHR) blocker in acromegaly patients induced colon p53 and adenomatous polyposis coli (APC), reversing progrowth GH signals. p53 was also induced in skin fibroblasts derived from short-statured humans with mutant GHR. GH-deficient prophet of pituitary-specific positive transcription factor 1 (Prop1)(-/-) mice exhibited induced colon p53 levels, and cross-breeding them with Apc(min+/-) mice that normally develop intestinal and colon tumors resulted in GH-deficient double mutants with markedly decreased tumor number and size. We also demonstrate that GH suppresses p53 and reduces apoptosis in human colon cell lines as well as in induced human pluripotent stem cell-derived intestinal organoids, and confirm in vivo that GH suppresses colon mucosal p53/p21. GH excess leads to decreased colon cell phosphatase and tensin homolog deleted on chromosome 10 (PTEN), increased cell survival with down-regulated APC, nuclear β-catenin accumulation, and increased epithelial-mesenchymal transition factors and colon cell motility. We propose that GH is a molecular component of the "field change" milieu permissive for neoplastic colon growth

Pooled safety analysis of evolocumab in over 6000 patients from double-blind and open-label extension studies

Background—Evolocumab, a fully human monoclonal antibody to PCSK9, markedly reduces LDL-C across diverse patient populations. The objective of this study was to assess the safety and tolerability of evolocumab in a pooled safety analysis from phase 2 or 3 randomized and placebo or comparator-controlled trials (integrated parent trials) and the first year of open-label extension (OLE) trials that included a standard-of-care control group. Methods—This analysis included adverse event (AE) data from 6026 patients in 12 phase 2 and 3 parent trials, with a median exposure of 2.8 months, and of those patients, from 4465 patients who continued with a median follow-up of 11.1 months in two OLE trials. Adverse events were analyzed separately for the parent and OLE trials. Overall AE rates, serious AEs (SAEs), laboratory assessments, and AEs of interest were evaluated. Results—Overall AE rates were similar between evolocumab and control in the parent trials (51.1% vs 49.6%) and in Year 1 of OLE trials (70.0% vs 66.0%), as were those for SAEs. Elevations of serum transaminases, bilirubin and creatine kinase were infrequent and similar between groups. Muscle-related AEs were similar between evolocumab and control. Neurocognitive adverse events were infrequent and balanced during the double-blind parent studies (5 events [0.1%], evolocumab groups vs 6 events [0.3%], control groups). In the OLE trials, 27 patients (0.9%) in the evolocumab groups and 5 patients (0.3%) in the control groups reported neurocognitive AEs. No neutralizing anti-evolocumab antibodies were detected. Conclusions—Overall, this integrated safety analysis of 6026 patients pooled across phase 2/3 trials and 4465 patients who continued in open-label extension trials for 1 year supports a favorable benefit-risk profile for evolocumab