👤 Erica L Goodrich

Highly effective therapies to reduce triglyceride levels are lacking. Olezarsen is an In this phase 3, international, double-blind, randomized, placebo-controlled trial, we enrolled patients with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) and randomly assigned them in a 1:3 ratio to a 50-mg or 80-mg cohort. The patients were then randomly assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the least-squares mean percent change in triglyceride level from baseline to 6 months among the patients with moderate hypertriglyceridemia, reported as the difference between each olezarsen dose group and the placebo group (the placebo-adjusted change). A total of 1349 patients (254 in the olezarsen 50-mg group, 766 in the olezarsen 80-mg group, and 329 in the placebo group) were included in the primary efficacy analysis. The median age was 64 years, 40% of the patients were women, and the median triglyceride level at baseline was 238.5 mg per deciliter (interquartile range, 190.5 to 307.5). At 6 months, the placebo-adjusted least-squares mean change in triglyceride level was -58.4 percentage points (95% confidence interval [CI], -65.1 to -51.7; P<0.001) in the olezarsen 50-mg group and -60.6 percentage points (95% CI, -67.1 to -54.0; P<0.001) in the olezarsen 80-mg group. The incidence of serious adverse events appeared to be similar across the trial groups. Among patients with moderate hypertriglyceridemia and elevated cardiovascular risk, treatment with olezarsen resulted in significantly greater reduction in triglyceride levels at 6 months than placebo. (Funded by Ionis Pharmaceuticals; ESSENCE-TIMI 73b ClinicalTrials.gov number, NCT05610280.). Show less

Reducing the levels of triglycerides and triglyceride-rich lipoproteins remains an unmet clinical need. Olezarsen is an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), a genetically validated target for triglyceride lowering. In this phase 2b, randomized, controlled trial, we assigned adults either with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) in a 1:1 ratio to either a 50-mg or 80-mg cohort. Patients were then assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the percent change in the triglyceride level from baseline to 6 months, reported as the difference between each olezarsen group and placebo. Key secondary outcomes were changes in levels of APOC3, apolipoprotein B, non-high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. A total of 154 patients underwent randomization at 24 sites in North America. The median age of the patients was 62 years, and the median triglyceride level was 241.5 mg per deciliter. The 50-mg and 80-mg doses of olezarsen reduced triglyceride levels by 49.3 percentage points and 53.1 percentage points, respectively, as compared with placebo (P<0.001 for both comparisons). As compared with placebo, each dose of olezarsen also significantly reduced the levels of APOC3, apolipoprotein B, and non-HDL cholesterol, with no significant change in the LDL cholesterol level. The risks of adverse events and serious adverse events were similar in the three groups. Clinically meaningful hepatic, renal, or platelet abnormalities were uncommon, with similar risks in the three groups. In patients with predominantly moderate hypertriglyceridemia at elevated cardiovascular risk, olezarsen significantly reduced levels of triglycerides, apolipoprotein B, and non-HDL cholesterol, with no major safety concerns identified. (Funded by Ionis Pharmaceuticals; Bridge-TIMI 73a ClinicalTrials.gov number, NCT05355402.). Show less

Biomarker measures of contaminant exposure and nutrient status can help increase understanding of the risks and benefits associated with the consumption of traditional foods by Inuit. While gene-environment and gene-nutrient interactions may help explain variations in biomarker measures, the role of genetic polymorphisms is largely understudied especially for vulnerable sub-populations. The aim of this study was to characterize the relationship between single nucleotide polymorphisms (SNPs) in key genes and blood concentrations of environmental chemicals and nutrients among Inuit. Blood samples from 665 individuals who participated in the Qanuippitaa Survey (Nunavik, Canada) in 2004 were analyzed for toxicants and nutrients. DNA was extracted and 140 SNPs in classes relevant to the toxicokinetics and/or toxicodynamics of the target contaminants and nutrients, and/or are involved in cardiovascular health and lipid metabolism were genotyped using the Sequenom iPLEX Gold platform. Geometric means (μg/L) of mercury (Hg), cadmium (Cd), lead (Pb), DDE, PCB-153, and selenium (Se) were 11.1, 2.8, 39.9, 2.9, 1.1 and 301.2, respectively. Red blood cell membrane levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were 5.1%/total fatty acid (TFA) and 1.3%/TFA respectively. Out of 106 SNPs which met our inclusion criteria, biomarker levels for Hg, Cd, Pb, DDE, PCB-153, DHA, and EPA differed (p < 0.05) by genotype for 20, 13, 12, 19, 21, 9 and 8 SNPs, respectively. Following Bonferroni correction (p < 0.0005), only 9 SNPs remained significant (rs2274976 in MTHFR, rs174602 in FADS2, rs7115739 and rs74771917 in FADS3, rs713041 in GPX4, rs2306283 and rs4149056 in SLCO1B1, rs1885301 in ABCC2/MRP2, and rs4244285 in CYP2C19; 5 associated with Hg, 2 with Pb, 2 with DDE, 4 with PCB-153, 1 with DHA). The findings suggest that polymorphisms in environmentally-responsive genes can influence biomarker levels of key toxicants and nutrients. While there are no immediate clinical or public health implications of these findings, we believe that such gene-environment and gene-nutrient studies provide a foundation that will inform and provide direction to future studies. Show less