Background: Genetic loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis. Methods: Adults with non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). The primary end point was placebo-adjusted percentage change from baseline in non-HDL-C at 24 weeks. Secondary end points included placebo-adjusted percentage changes from baseline in triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and ANGPTL3. Results: Two hundred eighty-six subjects were randomized: 44 to placebo and 242 to vupanorsen. The median age was 64 (interquartile range, 58-69) years, 44% were female, the median non-HDL-C was 132.4 (interquartile range, 118.0-154.1) mg/dL, and the median triglycerides were 216.2 (interquartile range, 181.4-270.4) mg/dL. Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL-C ranging from 22.0% in the 60 mg every 2 weeks arm to 27.7% in the 80 mg every 2 weeks arm (all P <0.001 for all doses). There were dose-dependent reductions in triglycerides that ranged from 41.3% to 56.8% (all P <0.001). The effects on LDL-C and ApoB were more modest (7.9%-16.0% and 6.0%-15.1%, respectively) and without a clear dose-response relationship‚ and only the higher reductions achieved statistical significance. ANGPTL3 levels were decreased in a dose-dependent manner by 69.9% to 95.2% (all P <0.001). There were no confirmed instances of significant decline in renal function or platelet count with vupanorsen. Injection site reactions and >3x elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively), and there was a dose-dependent increase in hepatic fat fraction (up to 76%). Conclusions: Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non-HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic f at fraction.

The use of radiographic contrast during cardiac catheterization can cause acute renal failure with an increase in morbidity and mortality. Prophylactic acetylcysteine plus intravenous hydration have been shown to prevent contrast-induced nephropathy (CIN) in patients with chronic renal failure undergoing computed tomography scan, who receive low doses of intravenous contrast. Whether the use of prophylactic acetylcysteine can decrease the incidence of CIN when larger doses of contrast are used remains to be determined. We sought to evaluate whether the prophylactic administration of acetylcysteine plus intravenous hydration is superior to intravenous hydration alone in prevention of CIN in patients with chronic renal failure undergoing cardiac catheterization and receiving moderate to high doses of intravenous contrast (> 1 cc/kg). Seventy-three consecutive patients with renal insufficiency who received intravenous hydration and 600 mg of acetylcysteine twice a day 24 hr before and the day of the cardiac catheterization were compared with 106 consecutive patients who received hydration alone. Baseline and 48-hr serum creatinine concentrations were compared between the two groups before and after cardiac catheterization. Multivariate and univariate analysis were performed to assess the effects of acetylcysteine and other clinical variables in the change of serum creatinine after the procedure. Both groups had comparable clinical characteristics and received similar volumes of intravenous hydration. The volume of contrast used was similar for the two groups (2.2 +/- 1.7 vs. 2.3 +/- 1.5 cc/kg; P = 0.67). A mean change in serum creatinine of 0.17 +/- 0.54 mg/dl for the acetylcysteine group vs. 0.19 +/- 0.40 mg/dl for the control group (P = 0.77) was observed at 48 hr. The incidence CIN was 13% in the acetylcysteine vs. 12% in the control group (P = 0.84). Acetylcysteine, whether analyzed with multivariate or univariate analysis, failed to demonstrate a significant effect in the change of serum creatinine after cardiac catheterization. In patients with chronic renal insufficiency, acetylcysteine in a dose of 600 mg twice a day before and after cardiac catheterization, along with intravenous fluids, is as effective as fluids alone in the prevention of CIN when moderate to high doses of contrast are used.

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