Dose-dependent efficacy of olezarsen in high-risk hypertriglyceridemia: A meta-analysis

Abstract

BACKGROUND

Olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III (apoC-III), has shown promise in reducing triglyceride (TG) levels in patients with high-risk hypertriglyceridemia. This meta-analysis evaluates the comparative efficacy of different dosing regimens.

AIM

To compare the efficacy and safety of olezarsen 80 mg vs 50 mg in patients with high-risk hypertriglyceridemia through a systematic review and meta-analysis of randomized controlled trials (RCTs).

METHODS

PubMed, the Cochrane Library, and Google Scholar were searched for RCTs comparing olezarsen 80 mg to 50 mg. Three studies were analyzed using RevMan 5.4.1 random-effects models to obtain mean difference (MD) with 95%CIs.

RESULTS

Olezarsen 80 mg showed statistically significant reduction in apoC-III (MD = -0.26; 95%CI: -0.51 to - 0.01; P = 0.04). Whereas no difference was seen in TG levels (MD = -0.72; 95%CI: -1.55 to 0.12; P = 0.09), low density lipoproteins (MD = -0.03; 95%CI: -0.16 to 0.10, P = 0.67), very low-density lipoproteins (MD = -0.09; 95%CI: -0.22 to 0.04; P = 0.18), non-high-density lipoproteins (HDL; MD = -0.16; 95%CI: -0.50 to 0.18, P = 0.35), HDL (MD = 0.05; 95%CI: -0.08 to 0.18; P = 0.44), apolipoprotein B (MD = -0.91; 95%CI: -2.70 to 0.88; P = 0.32), adverse effects [AEs; relative risk (RR) = 1.04; 95%CI: 0.96-1.11; P = 0.35], serious AE (RR = 1.40; 95%CI: 0.97-2.02; P = 0.07), hypersensitivity reaction (RR = 1.71; 95%CI: 0.51-5.75; P = 0.39), renal dysfunction (RR = 1.13; 95%CI: 0.62-2.04; P = 0.69), hepatic dysfunction (RR = 1.07, 95%CI: 0.55-2.09; P = 0.84) or thrombocytopenia (RR = 1.57; 95%CI: 0.28-8.75; P = 0.61).

CONCLUSION

Apart from a limited dose-dependent effect on apoC-III, higher dose is not associated with any definitive advantage or disadvantage, highlighting a need for further research.

Key Words: Olezarsen; Dose-dependent effectiveness; Side-effects; Apolipoprotein C-III; Hypertriglyceridemia

Core Tip: This meta-analysis of three randomized controlled trials is the first to directly compare olezarsen 80 mg vs 50 mg in patients with high-risk hypertriglyceridemia. While the 80 mg dose produced a statistically significant incremental reduction in apolipoprotein C-III (apoC-III), no significant differences were observed in triglyceride, non-high-density lipoprotein cholesterol, or safety outcomes. These findings suggest that higher dosing confers limited added benefit beyond apoC-III suppression, though equivalence cannot be established from the available evidence.

INTRODUCTION

Hypertriglyceridemia is a very common metabolic problem and an extensively studied risk factor for atherosclerotic cardiovascular disease and acute pancreatitis, especially in association with moderately to severely increased triglyceride (TG) levels[1-3]. People with hypertriglyceridemia from genetic disorders form a smaller cohort, which has high chances of experiencing recurring attacks of hypertriglyceridemia and pancreatitis, despite being on contemporary drugs for lowering lipids[4,5]. Statin drugs and many other drugs can effectively reduce low-density lipoprotein cholesterol, while hypertriglyceridemia remains prevalent in high-risk individuals, thus highlighting the importance of lipoproteins containing TG drugs[1,6].

Apolipoprotein C-III (apoC-III) is a central regulator of TG metabolism through inhibition of lipoprotein lipase activity and impaired hepatic clearance of TG-rich lipoproteins[7]. Genetic studies demonstrating markedly lower TG levels and reduced risk of hypertriglyceridemia-related complications among carriers of APOC3 loss-of-function variants have established apoC-III as a biologically validated therapeutic target[8,9]. Olezarsen, a hepatocyte-targeted, N-acetylgalactosamine-conjugated antisense oligonucleotide that suppresses hepatic apoC-III production, has demonstrated robust reductions in TG and apoC-III levels in phase 2 and phase 3 randomized trials, including patients with familial hypertriglyceridemia, with a generally favorable safety profile[10,11].

Notably, both 50 mg and 80 mg monthly dosing regimens of olezarsen have shown clinically meaningful efficacy; however, the optimal dose remains uncertain. Existing trials have primarily compared each dose with placebo and were not designed for direct dose-to-dose comparisons, leaving uncertainty regarding incremental efficacy and potential dose-related safety tradeoffs, an issue of particular relevance for patients requiring long-term therapy[10-13]. To address this gap, the present meta-analysis compares the efficacy and safety of olezarsen 80 mg vs 50 mg in randomized controlled trials (RCTs) of patients with high-risk and familial hypertriglyceridemia, with the aim of informing evidence-based dose selection for this emerging targeted therapy.

MATERIALS AND METHODS

Study design and objectives

This study was reported in accordance with PRISMA statement (Figure 1)[14]. The objective was to compare the efficacy and safety of olezarsen 80 mg as compared to olezarsen 50 mg, for the management of hypertriglyceridemia. The analysis integrated data from RCTs comparing the two doses of olezarsen. The protocol for this meta-analysis was registered and published with PROSPERO (ID: CRD420251249672).

Figure 1 PRISMA flow diagram representing breakdown of screened and included studies. PICO: Population, intervention, comparator, and outcome.

Literature search and data sources

A structured search strategy was applied across PubMed, the Cochrane Library, and Google Scholar to identify studies published up to October 2025. The search combined MeSH terms and keywords to formulate a search string: “(Olezarsen OR ApoC-III Inhibitors OR Lipid Lowering Drugs) AND (hypertriglyceridemia OR familial chylomicronemia OR familial hyperlipidemia OR hyperlipidemia) AND (Randomized controlled trials OR RCTs OR Phase 2b studies OR Phase 3 studies) AND (Efficacy OR Hyperlipidemia management OR Adverse Events OR Side Effects)”. Only clinical trials comparing hyperlipidemia patients on olezarsen 50 mg with olezarsen 80 mg were included. Clinical trials.gov was searched to screen for ongoing studies using the following words: Olezarsen, apoC-III inhibitors, lipid lowering agents, familial chylomicronemia, familial hyperlipidemia, hyperlipidemia, hyperlipidemia improvement, efficacy, adverse events or side effects.

Eligibility criteria and study selection

Eligible studies enrolled adult patients (aged 18 years or older) with familial hyperlipidemia with or without history of cardiac diseases who were treated with olezarsen 50 mg or olezarsen 80 mg. Only trials comparing the two groups were included. The outcomes included: Primary outcomes- reduction in TG level, reduction in non-high-density lipoproteins (HDL) level and reduction in apoC-III levels and secondary outcomes-thrombocytopenia, hypersensitivity reaction, kidney dysfunction, liver dysfunction, reduction in low density lipoproteins (LDL) level, and reduction in very low-density lipoproteins (VLDL) level. Studies were excluded if they lacked a comparator group, used olezarsen dose other than 50 mg or 80 mg, involved non-human subjects, or were not published in English. Title and abstract screening were conducted independently by two reviewers (Khattak R and Sohail R), followed by full-text assessment. Any disagreements were resolved through discussion or with input from a third reviewer (Khan Z).

Data collection and quality evaluation

Study characteristics and relevant outcome data were extracted using a predefined data collection form. Extracted variables included study design, population demographics duration of follow-up, and reported endpoints (Tables 1 and 2).

Table 1 Tabulated representation of baseline characteristics of included randomized controlled trials.

Trial name	Year	Type of study	Location	Total study population	Olezarsen 50 mg (n)	Olezarsen 80 mg (n)	Duration of study
Balance trials[13] 2024	2024	Randomized control trial	United States, Europe and Canada	44	21	23	49 weeks
Bridge-TIMI 73a[11]	2024	Phase 2b randomized control trial	United States	97	58	39	12 months treatment and 13 weeks follow up
Essence-TIMI 73b[12]	2025	Phase 3 randomized control trial	United States	1020	254	766	12 months of treatment and 13 weeks follow up

Table 2 Tabulated representation of baseline characteristic of included population, mean ± SD/n (%)/median (IQR).

Characteristics		Balance trial 2024		Bridge-TIMI 73a 2024		Essence-TIMI 2025
		Olezarsen 50 mg	Olezarsen 80 mg	Olezarsen 50 mg	Olezarsen 80 mg	Olezarsen 50 mg	Olezarsen 80 mg
Age (year)		43.2 ± 12.1	47.7 ± 13.3	63 (54-71)	60 (54-69)	63 (57-69)	64 (56-70)
Female		6 (29)	11 (50)	24 (41)	24 (62)	97 (38.2)	306 (39.9)
Race	White	17 (81)	17 (77)	54 (93)	52 (91)	240 (94.5)	713 (93.1)
	Black	0	2 (9)	3 (5)	5 (9)	2 (0.8)	34 (4.4)
	Hispanic or Latino	3 (14)	1 (5)	21 (36)	23 (40)	67 (26.4)	179 (23.4)
	Asian	3 (14)	3 (14)	1 (2)	0	6 (2.4)	8 (1.0)
BMI (kg/m2)		22.4 ± 3.5	25.1 ± 6.0	32.9	33.0	31.6 (28.3-34.9)	31.5 (28.5-35.9)
DM		3 (14)	7 (32)	37 (64)	30 (77)	151 (59.4)	468 (61.1)
Pancreatitis		15 (71)	17 (77)	2 (3)	0 (0)	-	-
Lipid panel (mg/dL)	ApoC-III	27.7 ± 10.5	27.5 ± 11.6	15.3 (12.0-19.3)	15.8 (13.2-18.7)	15.2 (12.3-18.8)	15.3 (12.9-18.3)
	Triglyceride	2684 ± 1235	2613 ± 1499	230.0 (182.5-331.5)	241.5 (179.5-357.5)	235.3 (186.5-309.5)	237.3 (191.5-306.0)
	LDL cholesterol	17.6 ± 8.5	22.8 ± 14.1	83.8 (59.5-106.0)	81.5 (62.0-104.5)	79.0 (58.0-112.0)	81.0 (60.0-107.3)
	Apolipoprotein B	65.2 ± 13.5	58.4 ± 7.2	90.8 (75.5-105.0)	94.0 (78.0-114.5)	89.5 (73.1-110.3)	90.7 (74.0-109.0)
	Non-HDL cholesterol	307.6 ± 101.8	262.9 ± 100.4	132.2 (103.5-156.5)	134.5 (110.0-161.5)	123.3 (97.5-158.0)	126.0 (99.5-155.5)

BMI: Body mass index; DM: Diabetes mellitus; ApoC-III: Apolipoprotein C-III; LDL: Low density lipoproteins; HDL: High-density lipoproteins.

Risk of bias

The risk of bias was evaluated using the ROB-2 for RCTs (Figure 2)[15-17]. Discrepancies in bias assessment were discussed among the authors until consensus was achieved.

Figure 2 Risk of bias assessment of included randomized controlled trials.

Statistical analysis

Meta-analytic pooling was performed using a random-effects model to address potential heterogeneity among included studies. Risk estimates were presented as relative risks (RRs) with 95%CIs. The I² statistic was used to quantify heterogeneity, with a threshold of > 50% indicating considerable heterogeneity[18]. Due to the limited number of included studies, funnel plot analysis for publication bias and meta-regression could not be performed. Statistical significance was defined as P < 0.05.

For evaluation of the certainty of the evidence, the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach was used, and the quality of evidence of the pooled estimates was judged as high, moderate, low, or very low according to the GRADE Working Group (Table 3)[19,20].

Table 3 Certainty of evidence assessment using Grading of Recommendations, Assessment, Development, and Evaluation.

No of studies	Study design	Certainty assessment					No of patients		Effect		Certainty	Importance
		Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Change in triglyceride level	Placebo	Relative (95%CI)	Absolute (95%CI)
Change in triglyceride level
3	Randomized trials	Not serious	Not serious	Not serious	Not serious	None	845	333	-	SMD 0.72 lower (1.55 lower to 0.12 higher)	High	Critical
Change in HDL
2	Randomized trials	Not serious	Not serious	Not serious	Not serious	None	823	312	-	SMD 0.05 higher (0.08 lower to 0.18 higher)	High	Critical
Change in VLDL
2	Randomized trials	Not serious	Not serious	Not serious	Not serious	None	823	312	-	SMD 0.09 lower (0.22 lower to 0.04 higher)	High	Critical
Change in apolipoprotein C-III level
3	Randomized trials	Not serious	Not serious	Not serious	Not serious	None	845	333	-	SMD 0.26 lower (0.51 lower to 0.01 lower)	High	Critical
Change in apolipoprotein B level
2	Randomized trials	Not serious	Not serious	Not serious	Not serious	None	823	312	-	SMD 0.91 SD lower (2.7 lower to 0.88 higher)	High	Critical
Any adverse events
3	Randomized trials	Not serious	Not serious	Not serious	Not serious	None	695/911 (76.3%)	261/355 (73.5%)	RR = 1.04 (0.96-1.11)	29 more per 1000 (from 29 fewer to 81 more)	High	Critical
Any serious adverse events
3	Randomized trials	Not serious	Not serious	Not serious	Not serious	None	123/911 (13.5%)	34/355 (9.6%)	RR = 1.40 (0.97-2.02)	38 more per 1000 (from 3 fewer to 98 more)	High	Critical
Hypersensitivity reaction
3	Randomized trials	Not serious	Not serious	Not serious	Not serious	None	45/911 (4.9%)	14/355 (3.9%)	RR = 1.71 (0.51-5.75)	28 more per 1000 (from 19 fewer to 187 more)	High	Critical
Renal dysfunction
2	Randomized trials	Not serious	Not serious	Not serious	Not serious	None	44/889 (4.9%)	16/334 (4.8%)	RR = 1.13 (0.62-2.04)	6 more per 1000 (from 18 fewer to 50 more)	High	Critical
Liver dysfunction
3	Randomized trials	Not serious	Not serious	Not serious	Not serious	None	32/911 (3.5%)	15/355 (4.2%)	RR = 1.07 (0.55-2.09)	3 more per 1000 (from 19 fewer to 46 more)	High	Critical
Thrombocytopenia
2	Randomized trials	Not serious	Not serious	Not serious	Not serious	None	29/889 (3.3%)	9/334 (2.7%)	RR = 1.57 (0.28-8.75)	15 more per 1000 (from 19 fewer to 209 more)	High	Critical

RR: Relative risk; HDL: High-density lipoproteins; VLDL: Very low-density lipoproteins; SMD: Standardized mean difference.

Ethical statement

Since this study used only data from previously published literature, ethical approval and informed consent were not applicable.

RESULTS

Primary outcomes

TG reduction: Compared with the 50 mg regimen, treatment with olezarsen 80 mg was associated with a numerically greater reduction in TG levels; however, this difference did not reach statistical significance [mean difference (MD) = -0.72; 95%CI: -1.55 to 0.12; P value = 0.09; I² = 94%]. The significantly high heterogeneity hinders the ability to draw conclusion from the result. The corresponding forest plot is shown in Figure 3A.

Figure 3 Primary efficacy outcomes. A-C: Dose comparison of olezarsen 80 mg vs 50 mg in regard to reduction in triglyceride level (A), non-high-density lipoproteins cholesterol level (B), and apolipoprotein C-III level (C).

Non-HDL cholesterol reduction: There was no statistically significant difference between olezarsen 80 mg and 50 mg in reduction of non-HDL cholesterol (MD = -0.16; 95%CI: -0.50 to 0.18; P value = 0.35; I² = 65%). The associated high heterogeneity in the setting of small population size, limits the generalizability of the outcome. The forest plot is presented in Figure 3B.

ApoC-III reduction: Olezarsen 80 mg resulted in a statistically significant greater reduction in apoC-III levels compared with the 50 mg dose (MD = -0.26; 95%CI: -0.51 to -0.01; P value = 0.04; I² = 44%). The forest plot for apoC-III reduction is shown in Figure 3C.

Secondary outcomes

Other lipid parameters: No statistically significant differences were observed between the two dosing regimens for other lipid measures, including LDL (MD = -0.03; 95%CI: -0.16 to 0.10; P value = 0.67; I² = 0%), VLDL (MD = -0.09; 95%CI: -0.22 to 0.04; P value = 0.18; I² = 0%), HDL (MD = 0.05; 95%CI: -0.08 to 0.18; P value = 0.44; I² = 0%), and apoB (MD = -0.91; 95%CI: -2.70 to 0.88; P value = 0.32; I² = 98%). Forest plots for these secondary lipid outcomes are shown in Figure 4.

Figure 4 Secondary lipid outcomes. A-D: Dose comparison of olezarsen 80 mg vs 50 mg in regard to reduction in low density lipoproteins level (A), very low-density lipoproteins level (B), high-density lipoproteins level (C) and apolipoprotein B level (D).

Safety outcomes: (1) Any adverse events: All included trials reported data on any adverse events. Pooled analysis demonstrated no statistically significant difference in the incidence of any adverse events between patients treated with olezarsen 80 mg and those receiving 50 mg (RR = 1.04; 95%CI: 0.96-1.11; P value = 0.35; I² = 0%). The forest plot is shown in Figure 5A; (2) Serious adverse events: Serious adverse events were reported across the included trials. There was no statistically significant difference between the olezarsen 80 mg and 50 mg groups (RR = 1.40; 95%CI: 0.97-2.02; P value = 0.07; I² = 0%). The corresponding forest plot is presented in Figure 5B; (3) Hypersensitivity reactions: Three trials reported hypersensitivity reactions. Pooled analysis showed no statistically significant difference between the olezarsen 80 mg and 50 mg regimens (RR = 1.71; 95%CI: 0.51-5.75; P value = 0.39; I² = 37%). The forest plot is shown in Figure 6A; (4) Hepatic safety: Hepatic dysfunction did not differ significantly between the two dosing regimens (RR = 1.07; 95%CI: 0.55-2.09; P value = 0.84; I² = 18%). The forest plot is presented in Figure 6B; (5) Renal outcomes: Renal dysfunction was reported in multiple trials, with no statistically significant difference between olezarsen 80 mg and 50 mg (RR = 1.13; 95%CI: 0.62-2.04; P value = 0.69; I² = 0%). The forest plot is shown in Figure 6C; and (6) Thrombocytopenia: Thrombocytopenia events were infrequent and did not differ significantly between the two groups (RR = 1.57; 95%CI: 0.28-8.75; P value = 0.61; I² = 42%). The forest plot is presented in Figure 6D.

Figure 5 Overall safety outcomes. A and B: Dose comparison of olezarsen 80 mg vs 50 mg in regard to any adverse events (A) and serious adverse events (B).

Figure 6 Specific safety outcomes. A-D: Dose comparison of olezarsen 80 mg vs 50 mg in regard to hypersenstivity reaction (A), hepatic dysfunction (B), renal dysfunction (C) and thrombocytopenia (D).

Patient and public involvement

Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.

DISCUSSION

Summary of our analysis

In this meta-analysis, higher-dose olezarsen achieved greater suppression of apoC-III compared with the lower-dose regimen; however, this did not translate into superior TG or non-HDL cholesterol reduction. Other lipid parameters similarly showed no meaningful differences between dosing strategies, and safety outcomes were comparable across doses.

Rationale behind our findings

The clinical significance of olezarsen dosing can be appreciated when the biology of apoC-III is considered. ApoC-III is involved in TG metabolism by inhibiting the function of lipoprotein lipase and blocking the clearance of TG-rich lipoproteins from the liver[7-9]. Inhibition of apoC-III, therefore, represents a logical approach to the management of hypertriglyceridemia and familial chylomicronemia syndromes[4,5].

While the degree of suppression of apoC-III should correlate with a higher degree of TG lowering, the lack of statistical difference in terms of TG and non-HDL cholesterol lowering between the two dosing regimens hints at a possible ceiling effect in the dose-response relationship. This may indicate that lower doses of antisense therapy are sufficient to achieve maximal functional blockade of apoC-III; any further reduction of apoC-III will have no additional physiological benefit on TG metabolism. Also, the high levels of heterogeneity between studies with respect to TGs and non-HDL cholesterol support the hypothesis that patient factors such as their individual TG load, genetic background, and metabolism of TG-rich lipoproteins play a major role[2,3].

High heterogeneity and its effect on result interpretation

One major limitation with the review is the clinical heterogeneity among the studies considered, mainly in regard to baseline TG concentrations and the population studied. BALANCE trial enrolled familial chylomicronemia syndrome patients with high TGs (> 2600 mg/dL), while Essence-TIMI 73b and Bridge-TIMI 73a enrolled patients with moderately high TGs (around 200-300 mg/dL)[11-13]. As such, these populations could have differential responses to apoC-III inhibition, thus confounding any potential dose-response relationship that might exist. Furthermore, few available trials with small sample sizes did not allow for subgroup analysis. Future research efforts will have to consider recruiting more homogeneous populations to determine the dose-response relationship for olezarsen.

Alignment with existing literature

This data supports previous mechanistic and clinical evidence showing that, although apoC-III downregulation is an important factor in reducing TGs, the effect of target inhibition on the resulting lipid response does not operate on a linear pathway[2,7,9]. It has been previously shown that there comes a point at which metabolic pathways responsible for the clearance of TGs become effectively inhibited to the point where additional doses have reduced effectiveness. The current study furthers this by providing comparisons between different clinical dosage levels.

Evidence from existing guidelines

Modern lipid treatment algorithms have highlighted that the aim of treatment in severe and familial hypertriglyceridemia is to prevent clinical events, especially acute pancreatitis, instead of lowering TGs incrementally[1,6,21-23]. In clinical practice, the selection of lipid lowering agents should be guided by sustained treatment adherence, treatment safety, and other patient-related factors[1,6]. Therefore, the lack of incremental benefit of TGs or non-HDL cholesterol with increased dose of olezarsen provides a rationale for dosing.

Approach trial and relation to volanesorsen

The findings of our analysis should also be interpreted in the context of the APPROACH trial[24] evaluating volanesorsen. While this study provides important evidence supporting apoC-III inhibition in patients with familial chylomicronemia syndrome, our results may not be directly generalizable to volanesorsen due to the limited number of available trials and differences in study design, patient populations, and dosing strategies. The inclusion of a small number of studies restricts robust comparative interpretation across agents, and conclusions regarding class effect should therefore be made cautiously. Further adequately powered trials directly evaluating volanesorsen and other apoC-III inhibitors are needed to clarify their relative efficacy and safety and to better define their role across different TG phenotypes.

Clinical implications

The inability of higher doses of olezarsen to produce significant improvements in TGs or non-HDL cholesterol levels and similar safety characteristics makes dosage selection crucial. Low dose treatment might yield favorable results from a metabolic perspective along with other positive factors such as cost-effectiveness and adherence. This is especially significant when one takes into consideration the marked heterogeneity seen in response to lipid treatment in various clinical trials, reinforcing the need for individualized dosing strategies.

Limitations

There are some limitations that need to be considered. The limited number of randomized studies and a small sample size may have decreased the power of the study for detecting clinically significant differences in dose. Furthermore, a high degree of heterogeneity observed in TG and non-HDL cholesterol results makes it difficult to interpret the findings. This probably stems from differences in baseline lipid levels, risk factors, and experimental designs. Thirdly, a relatively short follow-up period does not allow for evaluation of any clinical endpoints.

CONCLUSION

In summary, while the high-dose treatment seems to provide more effective apoC-III inhibition, it failed to demonstrate better efficacy for TG and non-HDL cholesterol reduction or better safety outcomes relative to the 50 mg treatment. Nevertheless, the results obtained from the analysis need to be carefully considered given that only a few clinical trials were used as the basis for the investigation, and there is considerable heterogeneity in the outcomes of lipids. Variations between the results could have been influenced by baseline TG concentrations, as well as the type of disease state and research design rather than actual differences in the response to doses of olezarsen. Additionally, further studies with longer follow-up and clinically meaningful endpoints should be conducted to better clarify the dose response to olezarsen.