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 (proprotein convertase subtilisin/kexin type 9), markedly reduces low-density lipoprotein cholesterol 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 2 OLE trials. AEs were analyzed separately for the parent and OLE trials. Overall AE rates, serious AEs, laboratory assessments, and AEs of interest were evaluated. RESULTS: Overall AE rates were similar between evolocumab and control in the parent trials (51.1% versus 49.6%) and in year 1 of OLE trials (70.0% versus 66.0%), as were those for serious AEs. Elevations of serum transaminases, bilirubin, and creatine kinase were infrequent and similar between groups. Muscle-related AEs were similar between evolocumab and control. Neurocognitive AEs were infrequent and balanced during the double-blind parent studies (5 events [0.1%], evolocumab groups versus 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 antievolocumab antibodies were detected. CONCLUSIONS: Overall, this integrated safety analysis of 6026 patients pooled across phase 2/3 trials and 4465 patients who continued in OLE trials for 1 year supports a favorable benefit-risk profile for evolocumab.

Abdominal adiposity, insulin resistance, and oxidized low-density lipoproteins in Latino adolescents.

Abdominal obesity and insulin resistance (IR) place youth at higher risk for premature cardiovascular disease (CVD), but the underlying mechanisms are not clear. In adults, abdominal obesity and IR contribute to the oxidation of low-density lipoprotein (LDL). Whether similar mechanisms are operational in Latino adolescents is unknown. Therefore, we determined whether IR and abdominal adiposity are associated with higher oxLDL concentrations in Latino adolescents. Data from 123 Latino adolescents (16.3 ± 2.5 years; female = 74) were used for the present analysis. Participants were assessed for waist circumference, fasting serum oxLDL, and insulin sensitivity by the whole body insulin sensitivity index. In separate linear regression models adjusting for age and sex, both waist circumference and insulin sensitivity were significant predictors of oxLDL (ß = 1.9; p = 0.002; R2 = 0.13, ß = -1.7; p = 0.006; R2 = 0.11, respectively). When insulin sensitivity and waist circumference were included in the same model, both remained independent predictors of oxLDL (ß = 1.7; p = 0.016 and, ß = -1.5; p = 0.055, respectively; R2 = 0.16). These results suggest that insulin resistance and abdominal adiposity are associated with higher levels of LDL oxidation which may be a mechanism contributing to increased CVD risk in Latino adolescents.