Apolipoprotein C3 (ApoC3) is a glycoprotein that normally increases levels of plasma triglycerides. Thus, Apo C3 inhibitors such as olezarsen and plozasiran result in reduction of triglycerides levels.  In 2 phase 3 clinical trials of patients having familial chylomicronemia syndrome (FCS), olezarsen 80 mg administered subcutaneously every 4 weeks decreased triglycerides by -43.5 % (95% CI, -69.1 to -17.9; P<0.001) after 6 months compared with placebo. Corresponding reduction with plozasiran 25 mg given every 3 months was -59% (95% CI, -90 to -28; P<0.001) after 10 months. In another 2 trials of patients with severe multifactorial chylomicronemia syndrome (MFS), the mean placebo-adjusted decreases in triglycerides levels ranged from 57% to 72% after 6 months of treatment with olezarsen and plozasiran. In previous studies, the 2 agents decreased incidence of acute pancreatitis by 82-85%. Olezarsen and plozasiran were generally well-tolerated. Yet, they cause mild worsening of glycemic control and increase levels of low-density lipoprotein-cholesterol (LDL-C). Olezarsen may also cause increase APOB levels in patients with FCS, mild thrombocytopenia and increase in hepatic fat. Olezarsen and plozasiran are the first drugs proved to substantially prevent hypertriglyceridemia-induced acute pancreatitis. Randomized trials are needed to establish their long-term efficacy and safety and their effects on cardiovascular (CV) outcomes and mortality. 

APOC3 is a 79 amino acid glycoprotein synthesized in the liver and to a lesser extent by enterocytes, that is transported in the circulation on the surface of plasma lipoproteins, mainly triglyceride-rich lipoproteins [1]. APOC3 increases plasma triglycerides by potent inhibition of lipoprotein lipase (LPL), the enzyme responsible for hydrolysis and clearance of triglycerides from the circulation [1]. In addition, APOC3 increases plasma triglycerides through LPL-independent pathway by reducing hepatic clearance of the remnants of triglyceride-rich lipoproteins [2]. Thus, inhibition of APOC3 may lower triglycerides levels through LPL-dependent and independent mechanisms. Two medications were recently developed for inhibition of synthesis of APOC3. The first is olezarsen, an antisense oligonucleotide, and plozasiran, a small interfering RNA. Recently, the Federal Drug Administration (FDA) approved olezarsen (Tryngolza) (dose 80 mg every month) on December 19, 2024, and plozasiran (Redemplo) (approved dose 25 mg every 3 months) on November 18, 2025 to reduce triglycerides in adults with FCS [2,3] Both drugs are given subcutaneously. Before the approval of these 2 agents, there was no available pharmacological therapy to decrease incidence of hypertriglyceridemia-induced pancreatitis. The main purpose of this review is to provide an appraisal regarding efficacy and safety of olezarsen and plozasiran based on data released from clinical trials [5-10].       

Effects of olezarsen and plozasiran in familial chylomicronemia syndrome 

FCS is a rare autosomal recessive disease characterized by absence of lipoprotein lipase (LPL) activity as results of loss of function in the 2 alleles (copies) in the gene encoding LPL or in other related genes that encode proteins activating LPL [11]. Hence, patients present with severe and persistent hypertriglyceridemia (usually > 880 mg/dl) predisposing to attacks of recurrent acute pancreatitis. Until approval of olezarsen and plozasiran, no effective therapy existed for FCS. Such approval was based on results of 2 phase 3 clinical trials, the Balance and Palisade trials that evaluated olezarsen and plozasiran, respectively for treatment of FCS (table 1) [5,6]. In the Palisade trial, 41% of patients did not have genetic confirmation of FCS but had clinically diagnosed persistent chylomicronemia consistent with the more common multifactorial chylomicronemia syndrome [6]. All subjects in the 2 trials continued with the recommended diet that consisted of limitation of daily caloric intake from fat to 10-15% [5,6]. As shown in table 1, in the Balance trial, olezarsen 80 mg every 4 weeks significantly decreased mean triglycerides levels by 43.5% compared with placebo at 6 months [5]. In the Palisade trial, plozasiran 25 mg every 3 months decreased median triglyceride levels by 63% compared with placebo [6].  Interestingly, the significant reduction in triglycerides levels with the 2 APOC3 inhibitors in patients with FCS lacking LPL activity supported the notion that APOC3 inhibition may lower triglycerides by LPL-independent mechanisms. In agreement with the latter notion, plozasiran lowered triglycerides irrespective of the demonstration of genetic defects causing disruption of LPL activity [12]. 

Effects olezarsen and plozasiran on severe hypertriglyceridemia

Severe hypertriglyceridemia defined as fasting triglycerides levels > 500 mg/dl, sometimes entitled “multifactorial chylomicronemia syndrome” (MCS), is far more common that FCS occurring in 1:500 to 1000 in the population [13]. MCS, as its name implies, is attributed to multiple factors such as obesity, uncontrolled type 2 diabetes, alcohol and estrogen intake, and genetic predisposition [13]. In 2 phase 3 trials, CORE-TIMI 72a and 72b (n=1061), Martson et al [9] evaluated olezarsen in patients with MCS with median triglycerides levels of 793 mg/dl (interquartile range 593 to 1248 mg/dl) at baseline (table 2). At 6 months, mean percentage reduction in triglycerides across the 2 trials were 54% to 72% versus placebo [9]. Similar results were obtained with plozasiran in a phase 2 b trial (SHASTA Study) of patients with MCS (table 2) [10]. 

Effects on moderate hypertriglyceridemia and mixed hyperlipidemia

In patients with moderate hypertriglyceridemia (baseline median triglycerides 238 mg/dl), olezarsen 80 mg decreased triglycerides levels by 60% compared with placebo after 6 months (table 2) [7]. In patients with mixed hyperlipidemia defined as triglycerides 150-499 mg/dl and either LDL-C ≥70 mg/dl or non-high density lipoprotein cholesterol (non-HDL-C) ≥ 100 mg/dl, plozasiran decreased triglyceride by 56% versus placebo after 6 months (table 2) [8]. 

Effects on lipid profile

As expected from their mechanisms of actions, olezarsen and plozasiran reduced APOC3 levels by 70-90% [5-10]. In patients with moderate and mixed hyperlipidemia, compared with placebo, they increased levels of high-density-lipoprotein cholesterol (HDL-C) by 45-50%, and decreased non-HDL-C by 22-25% [7,8]. Apolipoprotein B is a measure of the total concentration of lipoprotein particles in circulation [14]. Both olezarsen and plozasiran modestly reduced Apo B levels by 7 to 19% versus placebo in moderate, mixed, and severe hypertriglyceridemia (table 2). Yet, in FCS, olezarsen increased Apo B levels from 58 to 69 mg/dl at 6 months, whereas plozasiran had no effect (table 1) [5,6]. With respect to LDL-C levels, the effects of olezarsen and plozasiran depend in large part on baseline LDL-C values. Thus, in patients with FCS characterized by low baseline LDL-C in the 20-25 mg/dl range, olezarsen and prolaziran have caused an increase concentrations of LDL-C to mean levels close to 37-49 mg/dl, but individual values uncommonly exceeded the target of 55 mg/dl (table 1) [5,6]. Likewise, in patients with MCS with baseline LDL-C levels of 65-71 mg/dl, olezarsen caused a significant increase in mean LDL-C values by 37% to 62% versus placebo with many values exceeding 70 mg/dl after treatment (table 2) [9]. Similar results were generally reported with plozasiran in a smaller phase 2b trial (n=229) in patients with MCS and median baseline triglycerides of 897 mg/dl (table 2) [10]. On the other hand, in patients with moderate and mixed hyperlipdemia with mean baseline LDL-C values of 87-102 mg/dl, olezarsen and plozasiran did not have significant effects on LDL-C levels (table 2) [7,8]. Plozasiran had no effects on levels of the atherogenic lipoprotein a [10]. Effects of olezarsen on lipoprotein a were not reported. 

Effects of olezarsen and plozasiran on incidence of acute pancreatitis

As result of their substantial reducing effects on triglycerides circulating concentrations, olezarsen and plozasiran decreased the incidence of acute pancreatitis attacks in patients with severe hypertriglyceridemia. The reduction was highly significant and estimated to be 88% by olezarsen and 83% by plozasiran (table 1) [5,6]. Similarly, among patients with severe hypertriglyceridemia, reduction of attacks of acute pancreatitis was 85% and 82% with olezarsen and plozasiran, respectively (table 2) [9,10]. This high efficacy is reflected by the small number of patients needed to treat to prevent acute pancreatitis. For instance, 20 patients needed to be treated with olezarsen for 1 year to prevent one episode of acute pancreatitis [15]. Moreover, in the high-risk group of patients with baseline serum triglycerides of ≥880 mg /dl or who experienced acute pancreatitis in the past, only 4 patients are needed to treat for 1 year to prevent one episode of acute pancreatitis [15]. 

Table 1: Olezarsen and plozasiran for chylomicronemia syndrome

Abbreviations in table: FCS: familial chylomicronemia syndrome, Apo B: apolipoprotein B, LDL-C: low-density lipoprotein cholesterol

Table 2: Olezarsen and Plozasiran for moderate and severe hypertriglyceridemia

Abbreviations in the table Apo B: apolipoprotein B, LDL-C: low-density lipoprotein cholesterol, non-HDL cholesterol: non-high-density lipoprotein cholesterol 

Table 3. Differences between olezarsen and plozasiran

Abbreviations: Apo B: apolipoprotein B, FCS: familial chylomicronemia syndrome

Effects of olezarsen on symptoms of familial chylomicronemia syndrome 

In an open-label extension extension study of the Balance trial including genetically confirmed patients with FCS, Kessler et al [16] interviewed a subgroup of 18 patients about the effects of olezarsen on their symptoms. Fifteen of the 18 participants (83.3%) reported improvements of symptoms of FCS in general with olezarsen therapy. Thus, they exhibited amelioration of the following symptoms: abdominal pain (in 14 of 17 subjects; 82.4%), fatigue (in 7 of 12 subjects; 58.3%), diarrhea (in 6 of 10 subjects; 60.0%), vomiting (in 7of 8 subjects; 87.5%), and difficulty thinking (in 3 of 5 subjects; 60.0%). Interestingly, 8 of 15 subjects (53.3%) reported that episodes of acute pancreatitis were less frequent and less severe after using olezarsen. with reduced number of hospitalizations in 4 of these 15 subjects (26.7%). In addition, 15 of 18 patients (83.3%) indicated they were satisfied with olezarsen treatment [16]. 

Safety of olezarsen and plozasiran 

Effects of olezarsen and plozasiran on glycemic control

Hyperglycemia seems to be a common adverse effect shared by olezarsen and plozasiran that is mainly evident in patients with diabetes and prediabetes. In the olezarsen trial by Bergmark et al [7], median HbA1c values increased slightly but significantly in the subgroup of patients with diabetes from 7.0% at baseline to 7.3% with the 50 mg dose and from 6.8% to 7.0% with the 80-mg dose compared with no change with placebo, being 7.0% at baseline and after 6 months (P<0>

In patients with chylomicronemia, plozasiran increased HbA1c from 5.7% to 6.0?ter 12 months versus 6.1% to 6.2% with placebo [6] in. In another trial, worsening of diabetes (definition not provided) occurred 22% and 8% of patients receiving plozasiran and placebo, respectively [8]. No change in insulin resistance or β-cell function was demonstrated after the use of olezarsen or plozasiran in patients with or without diabetes [7,9]. The reasons of worsening glycemic control by olezarsen and plozasiran are unclear. The current hypothesis might be the increased hepatic gluconeogenesis as result of increased uptake of substrates by the liver [5-10]. 

Effects of olezarsen and plozasiran on transaminases

Both olezarsen and plozasiran mildly increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) that did not exceed 3 times the upper normal limit except in one patient receiving olezarsen [5]. 

Effects of olezarsen and plozasiran on hepatic fat

Hepatic fat was evaluated by magnetic resonant imaging (MRI) in a subgroup of patients showed a dose-related absolute increase of 2.3 percentage points with the 50-mg-olezarsen and 4.2 percentage points with the 80-mg dose after 12 months of treatment [9]. The causes and clinical significance of this increase in hepatic fat with olezarsen are unclear but could be due to accelerated shift of circulating triglycerides to the liver. Meanwhile, Gaudet et al [10] did not find significant effects of plozasiran on liver fat using the same methodology.

Miscellaneous adverse effects

In the trial of FCS, 3 of 43 patients receiving olezarsen discontinued the drug due to diarrhea, vomiting, chills, chest discomfort, trismus and flushing [5], Injection site reactions were more common with olezarsen and plozasiran than placebo but were mild and did not lead to drug discontinuation. Mild thrombocytopenia was reported with olezarsen use.  Thus, platelet count of < 100 P=0.03)>

Effects of olezarsen and plozasiran on cardiovascular events

No dedicated trials are available to address the effects of olezarsen and plozasiran on CV events and mortality. Few events occurred in the olezarsen trials. Thus, major CV events including CV death, myocardial infarction, ischemic stroke or arterial revascularization occurred in 2.0% (14 events in 705 subjects) and 2.5% (9 events in 356 subjects) with olezarsen and placebo, respectively [9]. In the trial by Bergmark et al [7] of patients with moderate hypertriglyceridemia, CV events occurred in 2.8% in the olezarsen-50 mg group, 5.7% in the 80 mg-group and 4.3% in the placebo group. Therefore, it is premature to draw a conclusion about the CV effects of olezarsen. CV events were not reported in plozasiran trials, but no deaths were observed [6,8,10]. Recently, Martson et al [17] examined coronary plaque progression as a marker of coronary atherosclerosis by computed tomography coronary angiography (CCTA) imaging study in a subgroup of patients (n=468) included in the olezarsen trial Essence-TIMI 73 b (table 2). The latter trial included subjects with moderate hypertriglyceridemia and increased CV risk (table 2). After 12 months, no difference was demonstrated in in non-calcified plaque volume (the primary outcome) between olezarsen-treated patients (n=349) and placebo-treated subjects (n=119) [17]. These negative results suggest that olezarsen has no beneficial effects on coronary artery atherosclerosis over 12 months of therapy in patients with high CV risk. However, a long-term randomized trial with hard CV outcomes should be performed to establish CV effects of olezarsen. 

Olezarsen versus Plozasiran

There are no head-to-head trials comparing the 2 APOC3 inhibitors olezarsen and plozasiran. While the 2 drugs seem to have similar in efficacy, some differences exist regarding their safety profile as well as their costs (see table 3). 

Future needs

Since the reduction in incidence of acute pancreatitis by olezarsen and plozasiran was substantial and consistent in different patient groups, their approved indications should not be limited to patients with FCS but also include the prevention of hypertriglyceridemia-induced pancreatitis in general, provided that severe hypertriglyceridemia is persistent despite correction of secondary causes (e.g. alcohol abstinence, diabetes control). Other needs include the effects of olezarsen and plozasiran on CV events and mortality, their safety use in children < 18>

The APOC3 inhibitors olezarsen and plozasiran effectively lower triglyceride levels and prevent hypertriglyceridemia-induced acute pancreatitis. They have favorable effects on most components of lipid panel, except for a mild rise in LDL-C concentrations. Their safety over 1 year of use is overall reassuring. Mild worsening of glycemic control with olezarsen and plozasiran and increase in hepatic fat by olezarsen may be concerning. Long-term randomized trials are urgently needed to examine the effects of olezarsen and plozasiran on CV events and mortality. 

The author has no conflict of interest to declare.