ApoC-III inhibition reduces triglycerides in patients at high risk for or with established ASCVD

Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk

Literature - Tardif JC, Karwatowska-Prokopczuk E, St Amour E et al. - Eur Heart J. 2022 Jan 13;ehab820. doi: 10.1093/eurheartj/ehab820.

Introduction and methods


Apolipoprotein C-III (apoC-III) is an important regulator of plasma triglyceride levels [1,2]. A study suggested that ApoC-III may exert proatherogenic effects, both directly by enhancing inflammation in the vessel wall or indirectly by fostering hypertriglyceridemia [3]. In addition, epidemiological studies have shown that apoC-III levels are associated with ASCVD risk and CV mortality [4-6].

Olezarsen is an N-acetyl-galactosamine (GalNAc)-conjugated, antisense oligonucleotide targeted to hepatic APOC3 mRNA. Olezarsen can thereby inhibit apoC-III production.

Aim of the study

This study evaluated the effect of apoC-III inhibition by olezarsen on triglyceride levels and triglyceride-rich lipoprotein (TRL) levels in patients with elevated fasting triglyceride levels (200-500 mg/dl or 2.26-5.65 mmol/L) who are at high risk for ASCVD or with established ASCVD.


This phase 2, dose-ranging, multi-center, randomized, double-blind, placebo-controlled trial randomized 141 patients to one of four treatment groups (olezarsen 10 mg or placebo subcutaneously every 4 weeks; olezarsen 15mg or placebo subcutaneously every 2 weeks, olezarsen 10mg or placebo subcutaneously every week, and olezarsen 50mg or placebo subcutaneously every 4 weeks). In each treatment group, patients were randomized in a 4:1 ratio to receive olezarsen or placebo. Patients received treatment for at least 6 months and up to 12 months. Post-treatment follow-up period was 13 weeks.


The primary efficacy endpoint was the percent change in fasting triglyceride levels from baseline to 6 months of treatment. Secondary endpoints included the percent change from baseline to 6 months of treatment in apoC-III, total cholesterol, LDL-c, HDL-c, non-HDL-c, VLDL-c, apoB, and apoA-I, and the proportion of patients who achieved serum triglyceride levels < 150 mg/dL (<1.7mmol/L) or triglyceride levels <100 mg/dL (<1.13 mmol/L).

Main results

Changes in triglyceride levels

  • Olezarsen reduced fasting triglyceride levels from baseline to 6 months of treatment in all treatment groups, with least-squares mean (LSM) changes of: -23% (95% CI -34 to -10) in those receiving a dose of 10 mg every 4 weeks, -56% (95% CI -62 to -49) at 15 mg every 2 weeks, -60% (95% CI -66 to -54) at 10 mg every week, and -60% (95% CI -65 to -53) at 50 mg every 4 weeks. In comparison, fasting triglyceride levels increased by 6% ( 95% CI -9 to 23) in the pooled placebo group (P-value for the comparison of olezarsen with placebo ranged from 0.0042 to <0.0001).
  • The corresponding absolute mean change in triglyceride levels from baseline to 6 months in olezarsen-treated individuals ranged from -58.8 (SD 102.4) mg/dL [-0.66 (SD 1.16) mmol/L] in those who received 10 mg every 4 weeks to -184.3 (SD 94.1) mg/dL [-2.08 (SD 1.06) mmol/L] in those who received 10 mg every week. Triglyceride levels increased in the pooled placebo group by 42.8 (SD 206.6) mg/dL [SD 0.48 (2.33) mmol/L].

Changes in atherogenic lipids and apolipoproteins levels

  • Changes in atherogenic lipids with the highest dose of 50 mg every 4 weeks compared with placebo at 6 months of treatment were -74% (95% CI -80 to -66) for apoC-III (P < 0.0001), -58% (95% CI -63 to -52) for VLDL-c (P< 0.0001), -20% (95% CI -29 to -9) for non-HDL-c (P= 0.009), -10% (-19 to -1) for apoB (P=0.024), 30% (95% CI 18 to 44) for HDL-c (P<0.0001), and 14% (95% CI 7 to 20) for apolipoprotein A-I (P <0.0001). There were no significant changes in LDL-c and total cholesterol.

Proportion of patients achieving triglyceride levels<150 mg/dL or <100 mg/dL

  • The percentage of olezarsen-treated patients achieving fasting triglyceride levels <150 mg/dL (<1.7 mmol/L) was 14% in the group that received 10 mg every 4 week, 65% in the group that received 15 mg every 4 weeks, 74% in the group that received 10 mg every week, and 91% in the group that received 50 mg every 4 weeks. Corresponding percentages for patients achieving fasting triglyceride levels <100 mg/dL (<1.13 mmol/L) were 0%, 26%, 22% and 45%. In the pooled placebo group, 4% of patients reached triglyceride levels<150 mg/dL and 0% reached <100 mg/dL.


  • Adverse event rates were similar between groups. There were no drug-related serious adverse events and there was no significant difference in flu-like symptoms compared with placebo. The most frequent adverse events in olezarsen-treated patients compared to placebo-treated patients were injection site erythema (15.6% vs. 0%), arthralgia (12.2% vs. 0%), nasopharyngitis (12.2% vs. 8.3%), and upper respiratory tract infection (11.1% vs. 8.3%).


This phase 2 study shows that targeting hepatic APOC3 mRNA with olezarsen in patients at risk of or with established ASCVD results in substantial reductions in fasting triglyceride levels, compared with placebo.


1. Norata GD, Tsimikas S, Pirillo A, Catapano AL. Apolipoprotein C-III: from pathophysiology to pharmacology. Trends Pharmacol Sci 2015;36:675–687.

2. Gaudet D, Brisson D, Tremblay K et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med 2014;371:2200–2206.

3. Taskinen MR, Packard CJ, Boren J. Emerging evidence that apoC-III inhibitors provide novel options to reduce the residual CVD. Curr Atheroscler Rep 2019;21:27.

4. Wyler von Ballmoos MC, Haring B, Sacks FM. The risk of cardiovascular events with increased apolipoprotein CIII: a systematic review and meta-analysis. J Clin Lipidol 2015;9:498–510.

5. van Capelleveen JC, Bernelot Moens SJ, Yang X et al. Apolipoprotein C-III levels and incident coronary artery disease risk: the EPIC-Norfolk prospective population study. Arterioscler Thromb Vasc Biol 2017;37:1206–1212.

6. Scheffer PG, Teerlink T, Dekker JM et al. Increased plasma apolipoprotein C-III concentration independently predicts cardiovascular mortality: the Hoorn Study.Clin Chem 2008;54:1325–1330.

Find this article online at Eur Heart J.

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