Reduction of ANGPTL3 mRNA levels with antisense oligonucleotide vupanorsen significantly lowered plasma triglyceride levels and other atherogenic lipoproteins in diabetic patients with hepatic steatosis and mild hypertriglyceridaemia. In addition, vupanorsen had a favourable safety and tolerability profile.
Prof. Daniel Gaudet (University of Montréal, Canada) presented the results of the multicentre, double-blind, placebo-controlled, dose-ranging phase 2 study . Type 2 diabetes patients (n=105) with hepatic steatosis and fasting triglyceride levels >150 mg/dL were included in 3 dosing strategy cohorts (both dose and timing were variables). Within each cohort, participants were randomised 3:1 to vupanorsen or placebo. The primary endpoint was percentage change from baseline in fasting triglyceride levels at week 24.
The primary outcome was met. In the pooled placebo group, triglyceride change increased by a mean of 16%, whereas triglyceride dropped by 36% in the 40 mg vupanorsen every 4 weeks group (P=0.03), by 53% in the 80 mg every 4 weeks group (P<0.0001), and by 47% in the 20 mg once weekly group (P=0.0009). The secondary endpoints of percentage change in ANGPTL3, total cholesterol, VLDL-cholesterol, non-HDL-cholesterol, and ApoC-III were significantly affected in all groups receiving vupanorsen compared with placebo. However, glycaemic control or hepatic steatosis markers were not affected by vupanorsen.
Regarding safety, injection site reactions were the most frequent treatment-emergent adverse events (TEAEs). Any TEAE occurred in 59.3% in the pooled placebo group and in 73.1% to 88.5% of the patients in the 3 vupanorsen groups. TEAEs leading to discontinuation occurred in 3.8% to 11.5% of patients in the vupanorsen groups compared with none in the placebo group. There were no effects of vupanorsen on platelet count, liver function markers, and renal function markers compared with placebo.
In conclusion, vupanorsen lowered triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia. Vupanorsen may provide a new strategy for reduction of residual CV risk.
- Gaudet D, et al. ANGPTL3 antisense oligonucleotide to lower triglycerides. Lipids session, ESC Congress 2020, 29 Aug.
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