Efficacy and safety of small interfering RNA (siRNA) therapies for hypertriglyceridemia and mixed dyslipidemia: an updated systematic review and meta-analysis

In patients receiving siRNA targeting ANGPTL3, triglycerides were significantly reduced compared with placebo (MD, −50.8%; 95% CI, −71.5 to −30.1).

“Compared with placebo, triglyceride levels were significantly reduced in patients receiving siRNA targeting ANGPTL3 (MD, −50.8%; 95% CI, −71.5 to −30.1)”

• cites Gaudet et al., 2024 sourceNot checked — no full text of the source
• cites Ray et al., 2025 sourceNot checked — no full text of the source
• cites Tardif et al., 2022 sourceDisputed

  The Key Question (p. 3) identifies this trial’s treatment as olezarsen, an antisense oligonucleotide targeting APOC3—not an siRNA targeting ANGPTL3. The discussion of ANGPTL3 (p. 11) describes siRNA studies as ongoing or future work; it does not report the claimed −50.8% placebo-adjusted result. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

In patients receiving siRNA targeting ANGPTL3, VLDL-C was significantly reduced compared with placebo (MD, −41%; 95% CI, −52.8 to −29.1).

“Compared with placebo, VLDL-C levels were significantly reduced in patients receiving siRNA targeting ANGPTL3 (MD, −41%; 95% CI, −52.8 to −29.1)”

• cites Ray et al., 2025 sourceNot checked — no full text of the source
• cites Tardif et al., 2022 sourceDisputed

  The Introduction (p. 4) identifies the study intervention as olezarsen targeting APOC3, not siRNA targeting ANGPTL3. The Results (p. 5) report a significant placebo-adjusted VLDL-C reduction of 58% (95% CI, 52% to 63%) for the highest monthly olezarsen dose, not the claimed 41% (95% CI, 29.1% to 52.8%). (LLM, conf=0.89)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites Bergmark et al., 2025 sourcePartly supported

  The Results (p. 7) report a significant placebo-adjusted VLDL-cholesterol reduction, but it was with olezarsen, not an ANGPTL3-targeting siRNA, and the reported reductions were −56.6 and −57.4 percentage points rather than −41%. The Discussion (p. 12) mentions an ANGPTL3-targeting siRNA only in connection with triglyceride reduction; it does not give the claimed VLDL-C estimate or confidence interval. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Current management strategies for hypertriglyceridemia and mixed dyslipidemia provide limited and inconsistent benefits in triglyceride lowering and cardiovascular outcomes.

“Current management strategies for HTG and mixed dyslipidemia provide limited and inconsistent benefits in TG lowering and cardiovascular outcomes, underscoring the need for more effective and durable approaches targeting TRL and apoB-containing lipoproteins (Filtz et al., 2024; Berglund et al., 2012; Chapman et al., 2011).”

• cites Filtz et al., 2024 sourcePartly supported

  The Fibrates section reports that ACCORD and PROMINENT found no cardiovascular-event benefit despite triglyceride reductions of 16% and 26%, and the Omega-3 Fatty Acids section describes mixed cardiovascular trial results (pages not provided). But the Current Treatments table reports substantial triglyceride reductions across several existing strategies. The source therefore supports inconsistent cardiovascular benefits, not a general claim that triglyceride lowering itself is limited or inconsistent. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Berglund et al., 2012 sourcePartly supported

  Section 3.4–3.5 (page not available) says the available drug classes have limitations and describes inconsistent or limited evidence for cardiovascular risk reduction. But the Fibrates section (page not available) reports a 30–50% triglyceride reduction, so the guideline does not support a general claim that triglyceride-lowering benefits are limited and inconsistent. It also does not establish that these limitations apply specifically to mixed dyslipidemia. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Chapman et al., 2011 sourcePartly supported

  The Clinical intervention studies section (page not provided) says statins leave residual cardiovascular risk and fibrate outcome trials have had variable results, supporting the claim about inconsistent cardiovascular benefits. But it also reports triglyceride reductions of 15–20% with statin–fibrate combination therapy and benefits in some patient subgroups. The blanket characterization of triglyceride-lowering benefits as limited is therefore too broad. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

GalNAc conjugation enables selective uptake of siRNA by hepatocytes through the asialoglycoprotein receptor.

“GalNAc conjugation enables selective uptake of siRNA by hepatocytes through the asialoglycoprotein receptor, resulting in more efficient liver targeting and improved potency and safety (Katzmann et al., 2020; Gao et al., 2023; Masson et al., 2024; Ward et al., 2022).”

• cites Katzmann et al., 2020 sourceSupported
• cites Gao et al., 2023 sourcePartly supported

  The Introduction (page not specified) describes RBD5044 as a GalNAc-conjugated siRNA that targets APOC3 mRNA in the liver. It does not state that hepatocytes selectively take it up or identify the asialoglycoprotein receptor as the mechanism. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Masson et al., 2024 sourceNot checked — no full text of the source

In patients receiving siRNA targeting ANGPTL3, HDL-C was significantly reduced compared with placebo (MD, −20.2%; 95% CI, −25.4 to −14.9).

“Compared with placebo, HDL-C levels were significantly reduced in patients receiving siRNA targeting ANGPTL3 (MD, −20.2%; 95% CI, −25.4 to −14.9).”

• cites Gaudet et al., 2024 sourceNot checked — no full text of the source
• cites Ray et al., 2025 sourceNot checked — no full text of the source
• cites Tardif et al., 2022 sourceCould not verify

  The Methods and results (p. 2) describe a trial of olezarsen targeting APOC3, not siRNA targeting ANGPTL3. The discussion (p. 11) refers to ANGPTL3-targeting siRNA studies as future work; our copy does not report the claimed HDL-C reduction or confidence interval. The HDL-C increase reported for olezarsen (p. 5) concerns a different treatment and does not contradict the siRNA claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

In patients receiving siRNA targeting APOC3, triglycerides were significantly reduced compared with placebo (MD, −53.6%; 95% CI, −58.8 to −48.4).

“triglyceride levels were also significantly reduced in patients receiving siRNA targeting APOC3 (MD, −53.6%; 95% CI, −58.8 to −48.4)”

• cites Gaudet et al., 2024 sourceNot checked — no full text of the source
• cites Ray et al., 2025 sourceNot checked — no full text of the source
• cites Tardif et al., 2022 sourcePartly supported

  The Methods and results (p. 2) and Primary endpoint (p. 5) report significant triglyceride reductions with olezarsen versus placebo. But the paper identifies olezarsen as an antisense oligonucleotide, not siRNA, and its reported dose-specific estimates do not establish the cited MD of −53.6% or 95% CI of −58.8 to −48.4. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

In patients receiving siRNA targeting APOC3, HDL-C was significantly increased compared with placebo (MD, 40.9%; 95% CI, 31.6 to 50.2).

“In contrast, patients receiving siRNA therapy targeting APOC3 had a significant increase in HDL-C levels (MD, 40.9%; 95% CI, 31.6–50.2)”

• cites Gaudet et al., 2024 sourceNot checked — no full text of the source
• cites Ray et al., 2025 sourceNot checked — no full text of the source
• cites Tardif et al., 2022 sourcePartly supported

  The Results (p. 5) report a significant HDL-C increase of up to 42% with olezarsen, and Table 2 (p. 10) reports a placebo-relative ratio of 1.42 (95% CI 1.28–1.57). But the Key Question (p. 3) identifies olezarsen as an antisense oligonucleotide, not siRNA, and the claimed 40.9% difference and 31.6–50.2 confidence interval are not the figures reported here. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

In patients receiving siRNA targeting APOC3, LDL-C was not significantly reduced compared with placebo (MD, 0.6%; 95% CI, −5.7 to 6.9).

“but LDL-C levels were not significantly reduced in patients receiving siRNA targeting APOC3 (MD, 0.6%; 95% CI, −5.7–6.9)”

• cites Gaudet et al., 2024 sourceNot checked — no full text of the source
• cites Ray et al., 2025 sourceNot checked — no full text of the source
• cites Tardif et al., 2022 sourcePartly supported

  The Results (p. 5) report no dose-dependent LDL-C effect with olezarsen, and the Discussion (p. 8) describes the LDL-C change as neutral. But the Introduction (p. 4) identifies olezarsen as an antisense oligonucleotide, not siRNA, and our copy does not report the cited MD of 0.6% or its 95% CI of −5.7 to 6.9. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In patients receiving siRNA targeting APOC3, non-HDL-C was significantly reduced compared with placebo (MD, −20.5%; 95% CI, −23.2 to −17.8).

“non-HDL-C levels were also significantly reduced in patients receiving siRNA targeting APOC3 (MD, −20.5%; 95% CI, −23.2 to −17.8)”

• cites Gaudet et al., 2024 sourceNot checked — no full text of the source
• cites Ray et al., 2025 sourceNot checked — no full text of the source
• cites Tardif et al., 2022 sourcePartly supported

  The Results (‘Changes in atherogenic lipids and apolipoproteins,’ p. 5) report a significant non-HDL-C reduction versus placebo, but give −20% (95% CI, −29 to −9) for the highest monthly dose, not the claimed −20.5% (−23.2 to −17.8). The Introduction (p. 4) identifies the treatment as olezarsen, an antisense oligonucleotide, not siRNA. (LLM, conf=0.94)

  Experimental — accuracy not yet measured

Compared with placebo, small interfering RNA therapy reduced non-HDL-C by a pooled mean difference of −21.9% (95% CI, −26.1 to −17.6; I2 = 56.1%), a statistically significant reduction.

“Compared with placebo, the pooled mean difference in Non-HDL-C was −21.9% (95% CI, −26.1 to −17.6; I2 = 56.1%), indicating a statistically significant reduction in Non-HDL-C with small interfering RNA therapy (Figure 5A).”

• cites Gaudet et al., 2024 sourceNot checked — no full text of the source
• cites Ray et al., 2025 sourceNot checked — no full text of the source
• cites Tardif et al., 2022 sourcePartly supported

  The Changes in atherogenic lipids and apolipoproteins section (p. 5) reports a statistically significant reduction in non-HDL-C versus placebo, but it is −20% (95% CI, −29 to −9) for one olezarsen dose, not the claimed pooled estimate of −21.9% (95% CI, −26.1 to −17.6; I² = 56.1%). The paper identifies olezarsen as an antisense oligonucleotide, not a small interfering RNA therapy (p. 2). (LLM, conf=0.90)

  Experimental — accuracy not yet measured

In patients receiving siRNA targeting ANGPTL3, LDL-C was significantly reduced compared with placebo (MD, −13.2%; 95% CI, −20.1 to −6.2).

“Compared with placebo, LDL-C levels were significantly reduced in patients receiving siRNA targeting ANGPTL3 (MD, −13.2%; 95% CI, −20.1 to −6.2)”

• cites Gaudet et al., 2024 sourceNot checked — no full text of the source
• cites Ray et al., 2025 sourceNot checked — no full text of the source
• cites Tardif et al., 2022 sourcePartly supported

  The discussion under Table 2 Continued (p. 11) says ANGPTL3 inhibition has potent effects on LDL-C, supporting the general direction of the claim. It does not report a placebo-controlled result for ANGPTL3-targeting siRNA or the stated −13.2% difference and confidence interval; it describes siRNA studies as ongoing or future work. The study itself evaluated the APOC3-targeting drug olezarsen (Discussion, p. 7). (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Compared with placebo, small interfering RNA therapy reduced VLDL-C by a pooled mean difference of −49.5% (95% CI, −60.1 to −38.9; I2 = 72.4%), a statistically significant reduction.

“Compared with placebo, the pooled mean difference in VLDL-C was −49.5% (95% CI, −60.1 to −38.9; I2 = 72.4%), indicating a statistically significant reduction in VLDL-C with small interfering RNA therapy (Figure 6A).”

• cites Ray et al., 2025 sourceNot checked — no full text of the source
• cites Tardif et al., 2022 sourcePartly supported

  The ‘Changes in atherogenic lipids and apolipoproteins’ section (p. 5) reports a significant VLDL-C reduction versus placebo, including −58% for one olezarsen dose. But the ‘Key Question’ (p. 3) identifies olezarsen as an antisense oligonucleotide, not a small interfering RNA, and the paper does not report the claimed pooled −49.5% estimate, confidence interval, or I². (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites Bergmark et al., 2025 sourcePartly supported

  The Results (p. 7) show significant placebo-adjusted reductions in VLDL-C with olezarsen, supporting the direction of the claim. But −49.5% is the change from baseline in one dose group, not a pooled difference versus placebo; the reported placebo-adjusted changes are −56.6 and −57.4 percentage points. The paper does not report the claimed pooled confidence interval or I², and its Discussion (p. 12) identifies a different therapy, plozasiran, as small interfering RNA. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Regulatory proteins such as APOC3 and ANGPTL3 play central roles in modulating lipoprotein lipase activity, hepatic lipoprotein production, and remnant metabolism.

“Regulatory proteins such as APOC3 and ANGPTL3 play central roles in modulating lipoprotein lipase activity, hepatic lipoprotein production, and remnant metabolism, providing a strong biological rationale for target-specific therapeutic strategies (Scicchitano et al., 2024).”

• cites Scicchitano et al., 2024 sourcePartly supported

  Section 3 identifies apoC-III as an inhibitor of lipoprotein lipase (LPL), and §4.1 says the ANGPTL3 pathway inhibits LPL; §3 also links LPL activity to chylomicron-remnant formation. But the paper does not attribute hepatic lipoprotein production or hepatic remnant uptake to APOC3 and ANGPTL3 as the claim suggests; §3 instead describes other factors in those processes. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Hypertriglyceridemia is a biologically heterogeneous condition arising from complex interactions between genetic predisposition and metabolic regulation.

“Hypertriglyceridemia is a biologically heterogeneous condition arising from complex interactions between genetic predisposition and metabolic regulation.”

• cites Scicchitano et al., 2024 sourceSupported

APOC3 inhibition primarily enhances peripheral clearance of triglyceride-rich lipoproteins without substantially affecting hepatic VLDL production or LDL metabolism.

“APOC3 inhibition primarily enhances peripheral clearance of triglyceride-rich lipoproteins without substantially affecting hepatic VLDL production or LDL metabolism, explaining neutral LDL-C effects and a tendency toward higher HDL-C levels (Malick et al., 2023b; Zhang, 2021; Visser et al., 2022; Khetarpal et al., 2017; Chen et al., 2024).”

• cites Malick et al., 2023bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Zhang, 2021 sourceCould not verify

  The Rationale and Weaknesses sections discuss ANGPTL3 and ANGPTL8, not APOC3. Searches for APOC3, apolipoprotein C-III, VLDL production, and LDL metabolism found no passage addressing the attributed mechanism or its claimed LDL-C and HDL-C effects. (LLM, conf=0.75)

  Experimental — accuracy not yet measured
• cites Visser et al., 2022 sourcePartly supported

  The APOC3 Antagonists section (page unavailable) says apoC-III is thought to inhibit lipoprotein lipase-mediated triglyceride lipolysis, supporting a role for APOC3 inhibition in clearing triglyceride-rich lipoproteins. It also says apoC-III interferes with hepatic clearance, so the source does not establish that the effect is primarily peripheral. The section does not establish negligible effects on VLDL production or LDL metabolism, or the proposed explanation for LDL-C and HDL-C changes. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

In patients receiving siRNA targeting APOC3, VLDL-C was significantly reduced compared with placebo (MD, −53.6%; 95% CI, −63.2 to −44).

“VLDL-C levels were also significantly reduced in patients receiving siRNA targeting APOC3 (MD, −53.6%; 95% CI, −63.2 to −44)”

• cites Ray et al., 2025 sourceNot checked — no full text of the source
• cites Tardif et al., 2022 sourcePartly supported

  The 'Changes in atherogenic lipids and apolipoproteins' section (p. 5) reports a significant VLDL-C reduction versus placebo, including −58% (95% CI, −63 to −52) for the highest monthly dose. But the Introduction (p. 4) identifies the treatment as olezarsen, an antisense oligonucleotide—not siRNA—and our copy does not report the claimed −53.6% estimate or its confidence interval. (LLM, conf=0.91)

  Experimental — accuracy not yet measured
• cites Bergmark et al., 2025 sourcePartly supported

  The Results table (p. 7) reports significant placebo-adjusted VLDL-C reductions with olezarsen, an APOC3-targeting treatment. But the reported estimates are −56.6 and −57.4 percentage points, with different confidence intervals—not −53.6% (95% CI, −63.2 to −44). The Discussion (p. 12) identifies plozasiran, rather than the treatment tested in this trial, as a small interfering RNA targeting APOC3; it does not report the claimed VLDL-C estimate for plozasiran. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

siRNA therapies significantly reduced triglycerides compared with placebo (MD −52%; 95% CI −57.9 to −46.2).

“siRNA therapies significantly reduced triglycerides (TG) (MD, −52%; 95%, −57.9 to −46.2)”

Eight RCTs involving 2,671 participants met the inclusion criteria.

“Eight RCTs involving 2,671 participants met the inclusion criteria.”

ANGPTL3-targeted therapies resulted in more substantial reductions in LDL-C compared with placebo (MD −13.2%; 95% CI −20.1 to −6.2).

“ANGPTL3-targeted therapies resulted in more substantial reductions in low-density lipoprotein cholesterol (MD, −13.2%; 95% CI, −20.1 to −6.2)”

siRNA therapies significantly reduced non-HDL-C compared with placebo (MD −21.9%; 95% CI −26 to −17.7).

“non-high-density lipoprotein cholesterol (non-HDL-C) (MD, −21.9%; 95%, −26 to −17.7)”

ANGPTL3-targeted therapies led to a reduction in HDL-C levels compared with placebo (MD −20.2%; 95% CI −25.4 to −14.9).

“ANGPTL3-targeted therapies led to a reduction in HDL-C levels (MD, −20.2%; 95% CI, −25.4 to −14.9)”

APOC3-targeted therapies had a neutral effect on LDL-C levels compared with placebo (MD 0.6%; 95% CI −5.7 to 6.9).

“APOC3-targeted therapies had a neutral effect on LDL-C levels (MD, 0.6%; 95% CI, −5.7–6.9)”

The systematic review and meta-analysis included 2,671 individuals from eight different studies.

“Our systematic review and meta-analysis included 2,671 individuals from eight different studies.”

siRNA therapies significantly reduced apoB compared with placebo (MD −12.6%; 95% CI −16.4 to −8.8).

“apolipoprotein B (apoB) (MD, −12.6%; 95%, −16.4 to −8.8)”

The interaction between ANGPTL3 and APOC3 targeting on LDL-C was statistically significant (p = 0.00001).

“(p for interaction = 0.00001)”

No significant differences were observed in the risk of adverse events between siRNA therapy and placebo (RR 1.02; 95% CI 0.96-1.09).

“No significant differences were observed in the risk of adverse events between siRNA therapy and placebo (RR, 1.02; 95% CI, 0.96–1.09).”

APOC3-targeted therapies significantly increased HDL-C levels compared with placebo (MD 40.9%; 95% CI 31.6-50.2).

“APOC3-targeted therapies significantly increased high-density lipoprotein cholesterol levels (MD, 40.9%; 95% CI, 31.6–50.2)”

siRNA therapies significantly reduced VLDL-C compared with placebo (MD −49.5%; 95% CI −60.1 to −38.9).

“very low-density lipoprotein cholesterol (VLDL-C) (MD, −49.5%; 95%, −60.1 to −38.9)”

The interaction between ANGPTL3 and APOC3 targeting on HDL-C was statistically significant (p = 0.00001).

“(p for interaction = 0.00001)”

siRNA therapies significantly reduced remnant cholesterol compared with placebo (MD −64.8%; 95% CI −81.7 to −47.9).

“remnant cholesterol (MD, −64.8%; 95%, −81.7 to −47.9)compared with placebo”

Ultimately, eight studies met the inclusion criteria and were included in the meta-analysis.

“Ultimately, eight studies met the inclusion criteria and were included in the meta-analysis”

No interaction was found between siRNA targets (ANGPTL3 vs APOC3) for the association with percent change in triglycerides (p for interaction = 0.8).

“No interaction was found (p for interaction = 0.8).”

There was an interaction between APOC3 and ANGPTL3 targets in the association between siRNA therapy and percent change in LDL-C (p for interaction = 0.003).

“Interaction analysis showed that there was an interaction between the APOC3 and ANGPTL3 targets in the association between small interfering RNA therapy and the percentage change in LDL-C (p for interaction = 0.003).”

There was an interaction between APOC3 and ANGPTL3 targets in the association between siRNA therapy and percent change in HDL-C (p for interaction = 0.00001).

“Interaction analysis showed that there was an interaction between the APOC3 and ANGPTL3 targets in the association between small interfering RNA therapy and the percentage change in HDL-C (p for interaction = 0.00001).”

Eight studies evaluated the percentage changes in lipid levels from baseline in patients with hypertriglyceridemia or mixed dyslipidemia receiving siRNA therapy compared to those receiving a placebo.

“A total of eight studies evaluated the percentage changes in lipid levels from baseline in patients with hypertriglyceridemia or mixed dyslipidemia receiving small interfering RNA (siRNA) therapy compared to those receiving a placebo”

No interaction was found between siRNA targets (ANGPTL3 vs APOC3) for the association with percent change in non-HDL-C (p for interaction = 0.4).

“No interaction was found (p for interaction = 0.4).”

In patients receiving siRNA targeting APOC3, apoB levels are significantly reduced compared with placebo (MD, −12.1%; 95% CI, −15.9 to −8.2).

“Compared with placebo, apoB levels were significantly reduced in patients receiving siRNA targeting ANGPTL3 (MD, −15%; 95% CI, −27.6 to −2.3), and apoB levels were also significantly reduced in patients receiving siRNA targeting APOC3 (MD, −12.1%; 95% CI, −15.9 to −8.2) (Figure 6B).”

For agents targeting APOC3, siRNA therapy is not associated with an increased risk of adverse events versus placebo (RR, 1.02; 95% CI, 0.95-1.09).

“This was consistent for agents targeting ANGPTL3 (RR, 1.01; 95% CI, 0.74–1.37) and APOC3 (RR, 1.02; 95% CI, 0.95–1.09), indicating an overall favorable tolerability profile (Figure 9B).”

There is no interaction between siRNA target (ANGPTL3 vs APOC3) and the effect on apoB (p for interaction = 0.7).

“No interaction was found (p for interaction = 0.7).”

Variations in baseline characteristics, background therapies, and outcome measurements contributed to moderate-to-high heterogeneity.

“Third, variations in baseline characteristics, background therapies, and outcome measurements contributed to moderate-to-high heterogeneity.”

No significant associations were observed between target or specific siRNA drug and intervention effects for outcomes other than HDL-C (all p > 0.05).

“Meta-regression analysis showed that both the target (p = 0.001) and the specific siRNA drug (p = 0.033) were associated with the intervention effect on HDL-C, while no significant associations were observed for other outcomes (all p > 0.05; Supplementary Table S3).”

In patients receiving siRNA targeting ANGPTL3, remnant cholesterol levels are significantly reduced compared with placebo (MD, −105.3%; 95% CI, −137.6 to −73).

“Compared with placebo, remnant cholesterol levels were significantly reduced in patients receiving siRNA targeting ANGPTL3 (MD, −105.3%; 95% CI, −137.6 to −73) and remnant cholesterol levels were also significantly reduced in patients receiving siRNA targeting APOC3 (MD, −57.9%; 95% CI, −73.4 to −42.3) (Figure 8B).”

There is an interaction between APOC3 and ANGPTL3 targets in the association between siRNA therapy and percentage change in remnant cholesterol (p for interaction = 0.01).

“Interaction analysis showed that there was an interaction between the APOC3 and ANGPTL3 targets in the association between small interfering RNA therapy and the percentage change in remnant cholesterol (p for interaction = 0.01).”

No interaction was found between siRNA targets (ANGPTL3 vs APOC3) for the association with percent change in VLDL-C (p for interaction = 0.105).

“No interaction was found (p for interaction = 0.105).”

In patients with hypertriglyceridemia and mixed dyslipidemia, siRNA therapy compared with placebo reduces apolipoprotein B (apoB) by a pooled mean difference of −12.6% (95% CI, −16.4 to −8.8).

“Compared with placebo, the pooled mean difference in apoB was −12.6% (95% CI, −16.4 to −8.8; I2 = 50.6%), indicating a statistically significant reduction in apoB with small interfering RNA therapy (Figure 7A).”

siRNA therapy is not associated with an increased risk of adverse events versus placebo (RR, 1.02; 95% CI, 0.96-1.09).

“In a meta-analysis of seven RCTs (Ray et al., 2025; Tardif et al., 2022; Bergmark et al., 2024; Stroes et al., 2024; Ballantyne et al., 2024; Rosenson et al., 2024; Bergmark et al., 2025), siRNA therapy was not associated with an increased risk of adverse events versus placebo (RR, 1.02; 95% CI, 0.96–1.09) (Figure 9A).”

For agents targeting ANGPTL3, siRNA therapy is not associated with an increased risk of adverse events versus placebo (RR, 1.01; 95% CI, 0.74-1.37).

“This was consistent for agents targeting ANGPTL3 (RR, 1.01; 95% CI, 0.74–1.37) and APOC3 (RR, 1.02; 95% CI, 0.95–1.09), indicating an overall favorable tolerability profile (Figure 9B).”

The specific siRNA drug is associated with the intervention effect on HDL-C (p = 0.033).

“Meta-regression analysis showed that both the target (p = 0.001) and the specific siRNA drug (p = 0.033) were associated with the intervention effect on HDL-C, while no significant associations were observed for other outcomes (all p > 0.05; Supplementary Table S3).”

In patients receiving siRNA targeting ANGPTL3, apoB levels are significantly reduced compared with placebo (MD, −15%; 95% CI, −27.6 to −2.3).

“Compared with placebo, apoB levels were significantly reduced in patients receiving siRNA targeting ANGPTL3 (MD, −15%; 95% CI, −27.6 to −2.3), and apoB levels were also significantly reduced in patients receiving siRNA targeting APOC3 (MD, −12.1%; 95% CI, −15.9 to −8.2) (Figure 6B).”

In patients with hypertriglyceridemia and mixed dyslipidemia, siRNA therapy compared with placebo reduces remnant cholesterol by a pooled mean difference of −64.8% (95% CI, −81.7 to −47.9).

“Compared with placebo, the pooled mean difference in remnant cholesterol was −64.8% (95% CI, −81.7 to −47.9; I2 = 85.5%), indicating a statistically significant reduction in remnant cholesterol with small interfering RNA therapy (Figure 8A).”

In patients receiving siRNA targeting APOC3, remnant cholesterol levels are significantly reduced compared with placebo (MD, −57.9%; 95% CI, −73.4 to −42.3).

“Compared with placebo, remnant cholesterol levels were significantly reduced in patients receiving siRNA targeting ANGPTL3 (MD, −105.3%; 95% CI, −137.6 to −73) and remnant cholesterol levels were also significantly reduced in patients receiving siRNA targeting APOC3 (MD, −57.9%; 95% CI, −73.4 to −42.3) (Figure 8B).”

The siRNA target is associated with the intervention effect on HDL-C (p = 0.001).

“Meta-regression analysis showed that both the target (p = 0.001) and the specific siRNA drug (p = 0.033) were associated with the intervention effect on HDL-C, while no significant associations were observed for other outcomes (all p > 0.05; Supplementary Table S3).”

ANGPTL3-directed agents provide broader lipid-lowering, including LDL-C reduction.

“siRNA therapies targeting APOC3 and ANGPTL3 effectively reduce triglycerides and atherogenic lipoproteins, with distinct lipid modulation profiles: APOC3-directed agents favor TG reduction and HDL-C increase, while ANGPTL3-directed agents provide broader lipid-lowering, including LDL-C reduction.”

siRNA therapies demonstrate significant efficacy in reducing triglycerides in patients with HTG and mixed dyslipidemia.

“siRNA therapies demonstrate significant efficacy in reducing triglycerides and improving lipid profiles in patients with HTG and mixed dyslipidemia.”

Compared with earlier antisense oligonucleotide approaches, siRNAs are associated with improved platelet safety.

“Compared with earlier antisense oligonucleotide approaches, siRNAs are associated with less frequent dosing and improved platelet safety (Tang et al., 2024).”

• cites Tang et al., 2024 sourceNot checked — no full text of the source

Both therapies demonstrate favorable safety profiles.

“Both therapies demonstrate favorable safety profiles.”

APOC3-targeted treatments increase HDL-C.

“APOC3-targeted treatments primarily reduce triglycerides while increasing HDL-C”

ANGPTL3-targeted therapies offer broader lipid modulation, including substantial reductions in LDL-C.

“whereas ANGPTL3-targeted therapies offer broader lipid modulation, including substantial reductions in LDL-C.”

The residual cardiovascular risk under statin therapy is largely attributable to elevated triglycerides and triglyceride-rich lipoprotein remnants, including non-HDL-C and apolipoprotein B.

“Importantly, even under statin therapy achieving low-density lipoprotein cholesterol (LDL-C) control, substantial residual cardiovascular risk persists, largely attributable to elevated triglycerides (TG) and triglyceride-rich lipoprotein (TRL) remnants, including non–HDL-C and apolipoprotein B (apoB) (Watts et al., 2023; Vasas et al., 2024; Hussain et al., 2020; Malick et al., 2023a).”

• cites Watts et al., 2023 sourceNot checked — no full text of the source
• cites Vasas et al., 2024 sourceNot checked — no full text of the source
• cites Hussain et al., 2020 sourceNot checked — no full text of the source

Among patients with hypertriglyceridemia and mixed dyslipidemia, siRNA therapies targeting APOC3 and ANGPTL3 have demonstrated favorable effects on non-HDL-C, apoB, and VLDL-C across phase I-III clinical trials.

“Among patients with HTG and mixed dyslipidemia, siRNA therapies targeting APOC3 and ANGPTL3 have demonstrated marked TG reductions and favorable effects on non–HDL-C, apoB, and very-low-density lipoprotein cholesterol (VLDL-C) across phase I–III clinical trials (Gaudet et al., 2024; Huynh, 2024; Ray et al., 2025; Bornfeldt, 2024; Schwabe et al., 2020; Lim, 2024).”

• cites Gaudet et al., 2024 sourceNot checked — no full text of the source
• cites Huynh, 2024 sourceNot checked — no full text of the source
• cites Ray et al., 2025 sourceNot checked — no full text of the source

Among patients with hypertriglyceridemia and mixed dyslipidemia, siRNA therapies targeting APOC3 and ANGPTL3 have demonstrated marked triglyceride reductions across phase I-III clinical trials.

“Among patients with HTG and mixed dyslipidemia, siRNA therapies targeting APOC3 and ANGPTL3 have demonstrated marked TG reductions and favorable effects on non–HDL-C, apoB, and very-low-density lipoprotein cholesterol (VLDL-C) across phase I–III clinical trials (Gaudet et al., 2024; Huynh, 2024; Ray et al., 2025; Bornfeldt, 2024; Schwabe et al., 2020; Lim, 2024).”

• cites Gaudet et al., 2024 sourceNot checked — no full text of the source
• cites Huynh, 2024 sourceNot checked — no full text of the source
• cites Ray et al., 2025 sourceNot checked — no full text of the source

Even under statin therapy achieving low-density lipoprotein cholesterol control, substantial residual cardiovascular risk persists.

“Importantly, even under statin therapy achieving low-density lipoprotein cholesterol (LDL-C) control, substantial residual cardiovascular risk persists, largely attributable to elevated triglycerides (TG) and triglyceride-rich lipoprotein (TRL) remnants, including non–HDL-C and apolipoprotein B (apoB) (Watts et al., 2023; Vasas et al., 2024; Hussain et al., 2020; Malick et al., 2023a).”

• cites Watts et al., 2023 sourceNot checked — no full text of the source
• cites Vasas et al., 2024 sourceNot checked — no full text of the source
• cites Hussain et al., 2020 sourceNot checked — no full text of the source

Compared with earlier antisense oligonucleotide approaches, siRNAs are associated with less frequent dosing.

“Compared with earlier antisense oligonucleotide approaches, siRNAs are associated with less frequent dosing and improved platelet safety (Tang et al., 2024).”

• cites Tang et al., 2024 sourceNot checked — no full text of the source

The previous meta-analysis by Kamrul-Hasan et al. (2024) insufficiently explored whether lipid-lowering effects differ between siRNA therapies targeting APOC3 and ANGPTL3.

“Moreover, a previous meta-analysis (Kamrul-Hasan et al., 2024) did not incorporate recently published trials, including emerging data on ANGPTL3-targeting agents such as solbinsiran, and insufficiently explored whether lipid-lowering effects differ between siRNA therapies targeting APOC3 and ANGPTL3.”

• cites Kamrul-Hasan et al., 2024 sourceNot checked — no full text of the source

siRNA therapies improve lipid profiles in patients with HTG and mixed dyslipidemia.

“siRNA therapies demonstrate significant efficacy in reducing triglycerides and improving lipid profiles in patients with HTG and mixed dyslipidemia.”

A previous meta-analysis (Kamrul-Hasan et al., 2024) did not incorporate recently published trials, including emerging data on ANGPTL3-targeting agents such as solbinsiran.

“Moreover, a previous meta-analysis (Kamrul-Hasan et al., 2024) did not incorporate recently published trials, including emerging data on ANGPTL3-targeting agents such as solbinsiran, and insufficiently explored whether lipid-lowering effects differ between siRNA therapies targeting APOC3 and ANGPTL3.”

• cites Kamrul-Hasan et al., 2024 sourceNot checked — no full text of the source

APOC3-targeted treatments primarily reduce triglycerides.

“APOC3-targeted treatments primarily reduce triglycerides while increasing HDL-C”

siRNA therapies lower triglyceride-rich lipoproteins through liver-targeted silencing of key regulatory genes.

“siRNA therapies lower triglyceride-rich lipoproteins through liver-targeted silencing of key regulatory genes (Pérez-Carrión et al., 2024; Rondinone, 2008; de Paula Brandão et al., 2020; Tian et al., 2025; Tsimikas, 2018).”

• cites Pérez-Carrión et al., 2024 sourceNot checked — no full text of the source
• cites Rondinone, 2008 sourceNot checked — no full text of the source
• cites de Paula Brandão et al., 2020 sourceNot checked — no full text of the source

Excluding any single study did not materially change the overall estimates of siRNA efficacy and safety relative to placebo.

“Leave-one-out sensitivity analysis showed that excluding any single study did not materially change the overall estimates of siRNA efficacy and safety relative to placebo (Supplementary Figure S1).”

Distinct RNAi targets yield divergent lipid profiles.

“Finally, PCSK9-directed siRNA therapy (inclisiran), which predominantly lowers LDL-C with modest triglyceride effects, further illustrates how distinct RNAi targets yield divergent lipid profiles (Khalil et al., 2025).”

The included clinical trials were conducted with high methodological quality.

“This indicates that the included clinical trials were conducted with high methodological quality, thereby enhancing the reliability of the findings (Supplementary Figure S2).”

Included participants were mainly from selective clinical trial populations, limiting representation of key subgroups such as non-Caucasian individuals, patients with severe liver or kidney dysfunction, or rare genetic conditions.

“Second, included participants were mainly from selective clinical trial populations, limiting representation of key subgroups (e.g., non-Caucasian individuals, patients with severe liver or kidney dysfunction, or rare genetic conditions).”

The included studies had minimal concerns regarding quality.

“Overall, our systematic review and meta-analysis revealed minimal concerns regarding the quality of the included studies.”

APOC3 inhibition explains neutral LDL-C effects and a tendency toward higher HDL-C levels.

“APOC3 inhibition primarily enhances peripheral clearance of triglyceride-rich lipoproteins without substantially affecting hepatic VLDL production or LDL metabolism, explaining neutral LDL-C effects and a tendency toward higher HDL-C levels (Malick et al., 2023b; Zhang, 2021; Visser et al., 2022; Khetarpal et al., 2017; Chen et al., 2024).”

siRNA therapy has an overall favorable tolerability profile.

“This was consistent for agents targeting ANGPTL3 (RR, 1.01; 95% CI, 0.74–1.37) and APOC3 (RR, 1.02; 95% CI, 0.95–1.09), indicating an overall favorable tolerability profile (Figure 9B).”

ANGPTL3 inhibition accounts for concurrent LDL-C reduction and modest HDL-C decrease.

“In contrast, ANGPTL3 inhibition accelerates triglyceride-rich lipoprotein processing and reduces LDL precursors while enhancing HDL catabolism, accounting for concurrent LDL-C reduction and modest HDL-C decrease (Zhang, 2021; Chen et al., 2024; Adam et al., 2020; Wang et al., 2015; Yasuda et al., 2010; Hooper and Burnett, 2013).”

These mechanistic distinctions provide a biological rationale for target-specific therapy selection.

“These mechanistic distinctions provide a biological rationale for target-specific therapy selection.”

The included studies demonstrated a low risk of bias across critical domains including randomization, allocation concealment, intervention adherence, completeness of outcome data, accuracy and impartiality of outcome measurements, and transparency in outcome reporting.

“A comprehensive assessment of all studies demonstrated a low risk of bias across critical domains, including randomization, allocation concealment, intervention adherence, completeness of outcome data, accuracy and impartiality of outcome measurements, and transparency in outcome reporting.”

PCSK9-directed siRNA therapy (inclisiran) predominantly lowers LDL-C with modest triglyceride effects.

“Finally, PCSK9-directed siRNA therapy (inclisiran), which predominantly lowers LDL-C with modest triglyceride effects, further illustrates how distinct RNAi targets yield divergent lipid profiles (Khalil et al., 2025).”

• cites Khalil et al., 2025 sourceNot checked — no full text of the source

These therapies are generally well tolerated.

“These therapies are generally well tolerated and represent promising, target-specific options for precision management of hypertriglyceridemia and mixed dyslipidemia.”

siRNA therapies targeting APOC3 and ANGPTL3 effectively reduce triglycerides and atherogenic lipoproteins.

“siRNA therapies targeting APOC3 and ANGPTL3 effectively reduce triglycerides and atherogenic lipoproteins, with distinct lipid modulation profiles: APOC3-directed agents favor TG reduction and HDL-C increase, while ANGPTL3-directed agents provide broader lipid-lowering, including LDL-C reduction.”