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Inclisiran and siRNA-Based Lipid Lowering: A New Frontier Including ANGPTL3 Inhibitors and Apo C III Inhibitors
*Corresponding author: Dr.Ramya Pechetty, Department of Cardiology, Apollo Spectra Hospital, Ameerpet, Hyderabad. ramyapechetty@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Pechetty R, Rao PS, Deb T, Shekar C, Deepthi K. Inclisiran and siRNA-Based Lipid Lowering: A New Frontier Including ANGPTL3 Inhibitors and Apo C III Inhibitors. Indian J Cardiovasc Dis Women. 2025;10:312-24. doi: 10.25259/IJCDW_55_2025
Abstract
Cardiovascular (CV) disease remains the leading cause of death worldwide. Dyslipidemia is a well-known risk factor for CV disease. The persistent rise in heart disease despite widespread use of statins highlights the limitations of current cholesterol management strategies. While statins are effective, underutilization and intolerance leave significant treatment gaps, especially in women. Women tend to develop greater side effects to statins and are also prone to genetic polymorphisms which make them statin under-responsive. Beyond low-density lipoprotein, other lipoprotein targets have been investigated such as triglycerides and lipoprotein(a) that may contribute to the patient’s residual CV risk. Fortunately, new drug classes targeting these varied lipid pathways have shown promise in lowering cholesterol levels and reducing the CV event rates. This review will discuss the mode of action, effectiveness, and recommendations of three new classes of drugs – inclisiran, anti-angiopoietin-like 3 drugs, and apolipoprotein C-III inhibitors. Their effectiveness in women will be discussed in a separate section.
Keywords
Angiopoietin-like 3
Apoprotein III
Cardiovascular disease
Familial chylomicronemia syndrome
High-density lipoprotein
Homozygous familial hypercholesterolemia
LDL receptors
Lipid-lowering therapy
Lipoprotein(a)
Low-density lipoprotein cholesterol
Proprotein convertase subtilisin kexin type 9
Triglycerides
INTRODUCTION
Death due to cardiovascular disease ranks the highest globally.[1] Majority of these deaths can be prevented by effective control of the risk factors.[2] One of the most established risk factors for cardiovascular disease is dyslipidaemia.[3] The 2025 Focused Update for the management of dyslipidemias has established the role of statins as the first line drug in managing cholesterol. However, there are a subset of patients who have severe dyslipidemia that is refractory to statins;[4] and despite receiving adequate statin therapy, some patients may develop cardiovascular disease. This has led to the identification of new targets such as triglycerides (TG), non-high-density lipoprotein (HDL) cholesterol, lipoprotein a (Lp(a)), which can address this unmet need to lower CV risk. Novel anti-lipid drugs that target various sites of lipid metabolism are being developed and evaluated to improve the outcomes of such patients. Figure 1 shows the different stages in the lipid cycle targeted by the novel lipid-lowering drugs, some of which are summarized as below-
- Different targets of anti-lipid drugs. (ACL:ATP citrate lyase, HMGCR: 3-hydroxy-3-methylglutaryl coenzyme reductase, FA: Fatty acid, TG: Triglyceride, MTP: Microsomal transfer protein, LIPA: lysosomal acid lipase, LDLR: low-density lipoprotein receptors, RGX-501: Gene therapy that corrects LDLR deficiency, PCSK9: Proprotein convertase subtilisin kexin type 9, CSL-112: infused APOA1 peptide, HDL: High-density lipo protein, ABCA1/G1: ATP-binding cassette protein A1 and G1, LCAT: Lecithin cholesterol acyl transferase, LDL: Low-density lipoprotein, APO: apolipoprotein, DGAT: Diacylglycerol O-acyltransferase, CM: Chylomicron, ANGPTL: Angiopoietin-like 3, APOC3: Apo-protein CIII)
Drugs targeting low-density lipoprotein (LDL) – ezetimibe, bempedoic acid, PCSK9 inhibitors, inclisiran, anti-apolipoprotein B (Apo B) drugs – mipomersen
Drugs targeting TG – microsomal TG transfer protein inhibitors – lomitapide, anti-apolipoprotein C-III (Apo CIII) drugs
Drugs targeting both – angiopoietin-like 3 (ANGPTL3) inhibitors.
This review will focus on inclisiran, ANGPTL3 inhibitors, and Apo CIII inhibitors.
INCLISIRAN
Inclisiran is a novel LDL-reducing drug which acts through the inhibition of Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9).
Mechanism of action
Inclisiran is a synthetic small interfering RNA (siRNA) with a double-stranded structure, targeting the complementary messenger RNA (mRNA) that codes for the PCSK9 protein. By preventing the translation, thus the production of PCSK9, Inclisiran inhibits the recycling of LDL receptors from the surface of the liver. Subsequently, there is an increase in the number of LDL receptors on the surface of the liver thereby enhancing the removal of LDL cholesterol from the blood [Figure 2].
- Mechanism of action of inclisiran. (LDL-CH: LDL Cholesterol, PCSK9: Proprotein convertase subtilisin kexin type 9)
The GalNAc ligand on inclisiran has high affinity to the asialoglycoprotein receptor expressed on the liver. This enables specific uptake of the drug by the liver where PCSK9 is synthesized. Once inclisiran is internalized, inclisiran is taken up by the RNA-induced silencing complex, which degrades the PCSK9 mRNA. This Inclisiran-RISC complex remains stable over a long period of time enabling twice-yearly administration of inclisiran.[5]
Dosage and administration
Inclisiran is available as an injectable SC solution of 284 mg/1.5 mL (prefilled syringe).
After the 1st dose, 2nd dose is given after 3 months and thereafter every 6 months.
Side effects
The most common side effect of Inclisiran is injection site reactions (5–10% cases). Most of them are mild and transient and do not require discontinuation of treatment. They tend to reduce with repeated injections. Diarrhea and headaches are occasionally reported. The role of inclisiran in worsening insulin resistance needs further evaluation.
Trials on Inclisiran
Effectiveness in cholesterol reduction
The ORION and VICTORIAN trial series have established the safety and efficacy of inclisiran in LDL-C reduction [Table 1].[6-11]
| Name of the trial | Inclusion criteria | Main results/status |
|---|---|---|
| ORION-1[6] | Adults with elevated LDL-C, CVD/high risk, on maximally tolerated LLT or statin-intolerant | Dose-dependent LDL-C and PCSK9 reductions; up to ~50% LDL-C drop at ~180 days; safe. |
| ORION-3[10] Long-term follow-up trial |
Long-term follow-up of participants in ORION-1 | LDL-C reduction by 30 weeks was 49.5%; Reduction sustained at 4 years (47.2%). |
| ORION-4 Ongoing trial |
ASCVD (MI, stroke, PAD), ~15,000 patients; on background therapy | Large outcomes trial; ongoing, event-driven, completion ~2026; no results yet. |
| ORION-5[7] | Homozygous FH; baseline LDL-C very high despite maximal LLT±apheresis | No significant LDL-C reduction versus placebo at day 150; safety similar. |
| ORION-9[8] Phase 3 double blind trial |
Heterozygous FH, LDL ≥100 mg/dL, on max statin±ezetimibe | ~39–50% LDL-C reduction; safety profile good; injection-site reactions more frequent. |
| ORION-10[9] Phase 3 RCT |
ASCVD, LDL >70 mg/dL, on statins | LDL-C reduction of 50–56% at 17 months; consistent and safe. |
| ORION-11[9] Phase 3 RCT |
ASCVD or risk equivalents. Refractory elevated LDL | ~46–50% reduction in LDL; safety similar; strong goal attainment. |
| ORION-8[11] Long-term follow-up trial |
Additional 3-year follow-up of ORION 9,10, and 11 trials | Average LDL-C reduction of ~50–78.4% achieved pre-specified LDL-C targets. |
| ORION-18 | Asian patients with ASCVD/high ASCVD risk, elevated LDL-C despite LLT | ~57% LDL-C reduction at day 330; 72% achieved ≥50% decrease; safety similar. |
| VICTORION-difference | High/very high CV risk, not at LDL-C goal despite optimized LLT | Day 360: ~59% versus ~24% LDL-C reduction; goal attainment~85% versus 31% |
| VICTORION-initiate[14] | ASCVD, Inclisiran first versus usual care | Day 330: ~60% versus ~7% LDL-C reduction; goal attainment much higher; safety good. |
| VICTORION-inception[16] | Post ACS with high LDL | 45.6% reduction in LDL at 11 months |
| VICTORION mono[17] | Treatment naïve without preexisting ASCVD | LDL reduction 46.5%, better than ezetimibe or placebo |
| VICTORION-intervention | Post-revascularization patients (PCI or limb) | Ongoing; no results yet. |
| VICTORION-inclusion | ASCVD or risk equivalent; LDL-C elevated despite therapy; diverse/under-represented populations | Ongoing; no results yet. |
| VICTORION-2 prevent[20] | Pre-existing ASCVD | Ongoing |
| VICTORION-1 prevent | High CV risk, primary prevention (no prior ASCVD) | Large event-driven trial; ongoing. |
| VICTORION-challenge | ASCVD/high risk, LDL-C ≥70 despite statins±ezetimibe; inclisiran versus bempedoic acid | Ongoing; results awaited. |
CVD: Cardiovascular disease, LDL-C: Low-density lipoprotein cholesterol, LLT: Lipid-lowering therapy, PCSK9: proprotein convertase subtilisin kexin Type 9, ASCVD: Atherosclerotic cardiovascular disease, CV: Cardiovascular disease, MI: Myocardial infarction, PAD: peripheral artery disease, FH: Familial hypercholesterolemia, ACS: Acute coronary syndrome, PCI: percutaneous coronary intervention
Key points in the pooled analysis of the major trials on inclisiran are summarized in Figure 3.[12,13,15]
- Key points of pooled analysis of trials on Inclisiran. (LDL: Low-density lipoprotein, HDL: High-density lipoprotein, MACE: Major adverse cardiac events, RCT: Randomised control trial).
Effectiveness in special groups
The ORION 18 study demonstrated similar effectiveness of inclisiran in Asian patients with atherosclerotic cardiovascular disease (ASCVD) or at high risk of ASCVD. In patients with chronic kidney disease, especially those with stage 4, inclisiran has shown potential, with the data from ORION-7 suggesting that it might be beneficial.
Effectiveness in CV event reduction
After the overwhelming reduction in LDL levels with inclisiran had been demonstrated, investigators studied the trials of inclisiran to evaluate whether the benefit in LDL reduction could be translated into clinical benefit.
Data from the ORION-9, ORION-10, and ORION-11 were evaluated for the major adverse cardiovascular event (MACE) rate, which is a composite of CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke rates. Over 18 months, among 3655 patients, 8.3% experienced MACE, including 2.0% rate of fatal and non-fatal MIs and 0.8% rate of fatal and non-fatal strokes. Inclisiran significantly reduced composite MACE (odds ratio [OR]: 0.74 [0.58–0.94]) but not fatal and non-fatal MIs (OR: 0.80 [0.50–1.27]) or fatal and non-fatal stroke (OR: 0.86 [0.41–1.81]).[18]
However, in a pooled meta-analysis including the ORION 1, 5, 9, 10, 11, 15, and VICTORION INITIATE trials, differences in the risk of major adverse CV events, MI, stroke, and CV mortality were not significant between the inclisiran and control groups. The rates of all-cause mortality were also similar.[15]
In this regard, the ORION 4 trial is underway. The ORION 4 is a multinational study, intended to be conducted at 180 clinical sites in the UK and the USA. It intends to involve 15,000 adults with pre-existing CV disease. Patients will be randomized to inclisiran versus placebo in a 1:1 ratio. It aims to evaluate the reduction in MACE rates with inclisiran over 5 years. The estimated completion for the ORION-4 trial’s primary endpoint is July 2026, with the study’s overall completion estimated to be around December 2049.[19]
VICTORION-2 PREVENT study is another similar phase 3 study designed to test the effectiveness of inclisiran in reducing MACE rates in patients with pre-existing CV disease. It is presently in the recruiting phase.[20]
Timeline of the major inclisiran trials is shown in Figure 4.
- Timeline of major inclisiran trials.
Inclisiran-key takeaway points
Inclisiran can be used in heterozygous (both familial and non-familial) hypercholesterolemia, where LDL is not in the recommended range, despite appropriate medical therapy
Diabetics, in high risk, very high risk or extremely high-risk categories, with refractory hyperlipidemia, inclisiran can be added to the preexisting lipid-lowering therapies
Inclisiran may be considered as the first choice over other lipid-lowering drugs in patients with ASCVD with uncontrolled lipids on maximally tolerated statin therapy
Inclisiran may be considered in post-acute coronary syndrome patients (within 5 weeks of discharge) with uncontrolled LDL despite statin therapy
Inclisiran may be considered in treatment naïve, adults with LDL of 100–190 mg/dL and 10-year ASCVD risk of <7.5%, even without pre-existing ASCVD, diabetes, or familial hypercholesterolemia (FH)
Inclisiran may reduce CV event rate and mortality and may be considered in patients with ASCVD to improve the long-term outcomes.
Guideline recommendations on inclisiran
2025 ESC guidelines recommend inclisiran for patients with uncontrolled LDL in spite of statin or other lipid-lowering therapies (CLASS 1 LEVEL A).[21]
ANGPTL3 INHIBITORS
ANGPTL3 inhibitors can lower both LDL and TG levels.
Mechanism of action
ANGPTL3 is a glycoprotein secreted by liver cells that inhibit the lipoprotein lipase (LPL) and endothelial lipase (EL) in tissues. Inhibitors of ANGPTL3 increase the LPL and EL activity, thereby allowing LPL and EL to enhance the clearance of very-LDL (VLDL) remnants through remnant receptors in the liver, resulting in the decrease of LDL-C levels in an LDLR-independent manner. There is a lowering of the total cholesterol and TG levels also [Figure 5].
- Mechanism of action of angiopoietin-like 3 inhibitors. (LDL: Low-density lipoprotein, VLDL/VLDL-C: Very low-density lipoprotein, EL: Endothelial lipase, LPL: Lipoprotein lipase, ANGPTL3: Angiopoietin-like 3 inhibitors)
Table 2 lists the different types of ANGPTL3 inhibitors.
| S. No. | Name | Features |
|---|---|---|
| 1 | Evinacumab | Monoclonal antibody targeting ANGPTL3 |
| 2 | Zodasiran | siRNA therapy against ANGPTL3, currently under investigation for mixed dyslipidemia |
| 3 | Solbinsiran | siRNA therapy that aims to reduce ANGPTL3 expression, shown to be effective in preclinical studies and early human trials |
| 4 | Vupanorsen | Discontinued due to side effects |
ANGPTL3: Angiopoietin-like 3, siRNA: Small interfering RNA
Evinacumab
Evinacumab is an intravenously administered monoclonal antibody targeting ANGPTL3. Evinacumab is approved by the FDA as an adjunctive therapy for patients with homozygous FH (HoFH) older than 5 years of age.
Dosage and administration
The recommended dose of evinacumab is 15 mg/kg, intravenous, once every 4 weeks.
Side effects
Injection site reactions are the most common side effects. Other side effects are hypersensitivity reactions, nasopharyngitis, nausea, influenza-like illness, dizziness, extremity pain, and rhinorrhea.
Clinical trials with evinacumab
Clinical trials demonstrated effective LDL reduction as summarized in Table 3.[22-26]
| Name of the trial | Inclusion criteria | Main results/status |
|---|---|---|
| ELIPSE HoFH trial (65 patients)[22] |
Age ≥12 years, with homozygous FH, LDL-C ≥70 mg/dL on LLT |
Mean LDL-C reduced by ~47% after 24 weeks, 53.5% reduction in patients with “null/null” variant. More adverse events in the placebo group. Absolute reduction in LDL level was 132.1 mg/dL. |
| Long-term study in HoFH[23] | Age ≥12 years with HoFH | By 24 weeks: mean LDL-C reduction ~43.6% (absolute 3.4 mmol/L) in overall population, i41.7% n adults, and 55.4% in adolescents; sustained up to 120 weeks. |
| Pediatric HoFH (511 years) Trial[24] | Children aged 511 with genetically or clinically confirmed HoFH with uncontrolled lipids | Mean LDL-C reductions 48%; 79% achieved ≥50% reduction; substantial absolute drop (~132 mg/dL). Good tolerability |
| Cardiovascular Outcome/Event-Free Survival in HoFH (Open-Label Extension in France) (“OLE ELIPSE HoFH”) | HoFH patients, stable lipidlowering therapy including apheresis; ≥age 12 yrs. | At 6 months: 56% LDLC reduction (absolute ~3.7 mmol/L), sustained over 3.5 years. No cardiovascular events in the evinacumab group versus 13 events (5/21≈24%) in control over~4 years. |
| Realworld effectiveness and safety of Evinacumab in children and adults with HoFH[25] | Retrospective cohort of 24 patients (age range 5–84 years) with genetically or clinically confirmed HoFH | Mean LDL-C reduction 53.2% (±4.1). More proportion achieving LDL of <70 mg/dL. Well tolerated with mild adverse effects |
| Evinacumab in Patients with Refractory Hypercholesterolemia[26] | Adults (18–80 years) with refractory hypercholesterolemia, defined as LDL ≥70 mg/dL in those with atherosclerosis or ≥100 mg/dL without atherosclerosis, despite maximally tolerated LLT | At week16, significant LDL-C reduction with both subcutaneous and intravenous administration. |
HoFH: Homozygous familial hypercholesterolemia, CVD: Cardiovascular disease, LDL-C: Low-density lipoprotein cholesterol, FH: Familial hypercholesterolemia, LLT: Lipid-lowering therapy
A long-term randomized clinical trial was done in patients with primary hypercholesterolemia (with either heterozygous FH or pre-existing ASCVD without FH) where a 2-week screening period followed by a 16-week double-blind treatment period for subcutaneous regimens or a 24-week double-blind treatment period for intravenous regimens, 48-week open-label treatment period for intravenous treatment only, and a 24-week follow-up period. At 72 weeks, evinacumab, 15 mg/kg, reduced mean LDL-C level by 45.5%, reduced mean Apo B by 38.0%, non-HDL cholesterol by 48.4%, total cholesterol by 42.6%, and median fasting TG by 57.2%. Serious adverse events occurred in 9.4%, which were unrelated to the drug.[27]
Evinacumab-key takeaway points
Evinacumab is indicated in homozygous familial hypercholesterolemia refractory to statin therapy and/or other lipid-lowering therapies
Evinacumab may be considered in those with refractory hypercholesterolemia, including those with heterozygous FH
Evinacumab may be considered in those with established clinical ASCVD without FH.
Guideline recommendation for Evinacumab
The ESC 2025 guidelines recommend evinacumab in patients with HoFH, with high LDL despite statins and PCSK9.[21]
APO CIII INHIBITORS
Apo CIII inhibitors primarily lower TGs.
Mechanism of action
Apo CIII is a 79 amino acid glycoprotein synthesized principally in the liver and is an important component of VLDL, LDL, Lp (a), and HDL particles. Apo CIII inhibits the enzyme LPL and inhibits the hepatic uptake of TG-rich lipoprotein (TRL) remnants and LDL particles. Apo C III also increases the release of VLDL from the liver. Inhibition of Apo CIII thereby increases the LPL activity and facilitates the hepatic uptake and clearance of TRL remnant particles and LDL, leading to lowering of their plasma levels [Figure 6].
- Mechanism of action of apolipoprotein C-III inhibitors. (LDL: Low-density lipoprotein, TRL: Triglycerides-rich lipoprotein, LPL: lipoprotein lipase, HL: Hepatic lipase, VLDL: Very low-density lipoprotein, SDC1: Syndecan-1, LRP1: LDLR-related protein 1, LDLR: LDL receptor)
Examples of Apo CIII inhibitors are summarized in Table 4.
| S. No. | Name | Feature |
|---|---|---|
| 1 | Volanesorsen | Antisense oligonucleotide that inhibits Apo CIII |
| 2 | Olezarsen | Antisense oligonucleotide that reduces Apo C-III production |
| 3 | Plozasiran | Small interfering RNA that works similarly to olezarsen and is in advanced clinical development. |
Apo CIII: Apolipoprotein C-III
Volanesorsen
Volanesorsen is an antisense oligonucleotide that reduces the synthesis of Apo C-III.
Dosage and administration
It is administered subcutaneously at 100–400 mg once a week, with subsequent doses after 3 months.
Side effects
Mild-to-moderate injection-site reactions and thrombocytopenia are the most common side effects.
Effectiveness in TG reduction
In a phase 2 trial, patients with elevated fasting TG levels of 350–2,000 mg/dL and patients with fasting TG levels of 225–2,000 mg/dL refractory to fibrate therapy, volanesorsen 100, 200, or 300 mg SC weekly was given for 13 weeks. There were significant dose-dependent reductions in Apo CIII by ~80% in the single treatment group and ~71% as an add-on to fibrates. There was also a 31.3–70.9% reduction in TG levels and a 45.7% increase in HDL-C. There was a dose-dependent elevation in LDL-C; however, non-HDL-C or ApoB levels remained the same.[28] Trials establishing the safety and efficacy of volanesorsen are summarized in Table 5.[29-32]
| Name of the trial | Inclusion criteria | Main results/status |
|---|---|---|
| APPROACH trial (RCT)[29] - 66 patients |
Adults (≥18 years) with familial chylomicronemia syndrome (FCS) - fasting TG ≥750mg/dL 300 mg SC weekly injections of volanesorsen or placebo. |
77% reduction in TG versus ~18% increase in placebo at 3 months. Significant reduction in ApoC III (84% versus increase of 6.1%); marked reductions in pancreatitis events; thrombocytopenia (77%) and injection-site reactions observed. No severe thrombocytopenia noted |
| COMPASS trial[30] -113 patients |
Adults (≥18 years) with multifactorial severe hypertriglyceridemia (TG level between 500 and 1,261 mg/dL) or FCS and fasting TG ≥500mg/dL | Mean TG reduction 71.2% at 3 months versus 0.9% in placebo. Mean absolute TG drop ~869 mg/dL. Sustained effect up to 26 weeks. Side effects-injectionsite reactions, one case of very low platelets (<50,000/µL), one case of serum sickness. |
| VOL4002 study[31] | 22 adults from the APPROACH and/or APPROACH-OLE trials were followed up to assess the long-term effectiveness of volanesorsen | Apart from a significant and sustained reduction in triglyceride levels, a 74% reduction in pancreatitis rates was found compared to the prior 5 years |
| OpenLabel Extension in FCS (APPROACH and COMPASS populations+treatmentnaïve) | Extended follow-up for 12-24 months to assess longer-term safety and efficacy | Sustained reductions in TG over time in all groups, nearly 50–66% at 24 months |
| BROADEN study[32] - 40 patients |
Adults with familial partial lipodystrophy (FPLD) with concomitant elevated TG and diabetes weekly SC volanesorsen 300 mg or placebo for 52 weeks. | TG reduction at 3 months was 88% in the volanesorsen group and 22% in the placebo group. 53% reduction in hepatic fat fraction, some effects on glycated hemoglobin. Safety profile consistent with other studies |
TG: Triglycerides, RCT: Randomized controlled trial, Apo CIII: Apolipoprotein C-III, APPROACH: A Randomized, Double-Blind, Placebo-Placed, Controlled, Healthcare-based trial
Volanesorsen-key takeaway points
Volanesorsen is indicated for patients with familial chylomicronemia syndrome and severe hypertriglyceridemia
There is potential to extend its use for other causes of hypertriglyceridemia and familial partial lipodystrophy.
Recommendation on volanesorsen
Volanesorsen was approved by the European Union in May 2019 to treat adults with familial chylomicronemia syndrome with uncontrolled TG levels. However, due to the increased risk of thrombocytopenia, it has not been approved by the US FDA.
Olezarsen
Olezarsen is an antisense oligonucleotide that degrades the Apo C-III mRNA in the liver, thereby lowering the ApoCIII levels.
Dosage and administration
It is given as a subcutaneous, monthly once (80 mg/0.8 mL) injection.
Side effects
Injection site reactions, thrombocytopenia, and arthralgias are the most common side effects. Increased fasting glucose levels and elevated liver enzymes can occur rarely.
Effectiveness in TG reduction
Clinical trials of safety and efficacy with olezarsen are summarized in Table 6.[33-35]
| Name of the trial | Inclusion criteria | Main results/status |
|---|---|---|
| BALANCE study[33] -Double-blind, placebo-controlled trial - 66 patients - Olezarsen 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 49 weeks |
Adults with familial chylomicronemia syndrome (FCS), with fasting triglyceride levels≥880 mg/dL | 80mg reduced fasting TG by 42.5% (P≈0.0084). 50 mg reduced by 21.5% (not statistically significant). Apo CIII levels decreased significantly (73.7% with 80 mg, 65.5% with 50 mg) Fewer acute pancreatitis events.Favorable safety profile. |
| BRIDGE-TIMI 73a trial[34] | Adults with hypertriglyceridemia: either “moderate” (TG 150–499 mg/dL) plus elevated cardiovascular risk, or “severe” elevation of TG (TG ≥500mg/dL) | By 6 months, 50-mg reduced TG by 49.3% and 80-mg reduced TG levels by 53.1% Significant reduction in Apo CIII, Apo B, and non-HDL cholesterol levels, no change in the LDL-C. Adverse events similar in the three groups |
| ESSENCETIMI 73b trial[35] | Adults with either TG 150499 mg/d)+elevated cardiovascular risk (ASCVD or high risk), or TG ≥500 mg/dL |
At 6 months, TG reductions: 58.4% (50 mg) and 60.6% (80 mg) versus placebo. At 12 months, TG reduction 50.7% in both dose groups. Injection site reactions and mild liver enzyme elevations seen. |
TG: Triglycerides, RCT: Randomized controlled trial, Apo CIII: Apolipoprotein C-III, LDL-C: Low-density lipoprotein cholesterol, ASCVD: Atherosclerotic cardiovascular disease
Systematic review and meta-analysis of randomized controlled trials (RCTs) comparing olezarsen vs placebo in patients with dyslipidemia showed a significant reduction in ApoCIII across dosages, significant TG reduction, 49–50% reduction with 50 mg, and 52% with 80 mg. Suggests a 50 mg dose (very 4 weeks) may be near optimal; higher dose yields diminishing incremental benefit.
Olezarsen-key takeaway points
Olezarsen is indicated in familial chylomicronemia syndrome with elevated TG levels
Olezarsen may be used for those with TG 150– 499 mg/dL and elevated CV risk, or severe hypertriglyceridemia with TG >500 mg/dL.
Recommendation of Olezarsen
Olezarsen can be used as an adjunct to diet for adults with familial chylomicronemia syndrome. It was approved by both the U.S. FDA and the European Union for the same.
Plozasiran
Plozasiran is a small interfering RNA targeting the hepatocyte Apo CIII.
Dosage and administration
10 mg/25 mg/50 mg subcutaneously every 3 months.
Side effects
Abdominal pain, nasopharyngitis, headache, and nausea are the most common side effects. Hyperglycemia can occur in those with prediabetes or diabetes.
Effectiveness in TG reduction
In a 48-week RCT, plozasiran was evaluated in patients with mixed hyperlipidemia (TG 150–499 mg/dL and either LDL ≥70 mg/dL or non-HDL cholesterol ≥100 mg/dL). Plozasiran was given in the dose of 10 mg, 25 mg, or 50 mg on day 1 and 12th week (quarterly doses) or 50 mg of plozasiran on day 1 and 24th week (half-yearly doses). A significant dose-dependent reduction in the fasting TG level was observed with plozasiran (62.4% with the 50-mg-quarterly dose and 44.2% with the 50-mg-half-yearly dose). Worsening glycemic control was the most observed side effect.[36]
SHASTA-2 trial was a landmark multi-center trial where 2 subcutaneous doses of plozasiran (10, 25, or 50 mg) or matched placebo were given day 1 and 12th week to adults with severely elevated TG levels (500–4000 mg/dL). A follow-up was done until 48 weeks. Trials with plozasiran are summarized in Table 7.[37,38]
| Name of the trial | Inclusion criteria | Main results/status |
|---|---|---|
| Plozasiran for mixed hyperlipidemia | Adults with mixed hyperlipidemia: TG 150499 mg/dL with either LDLC ≥70 mg/dL or nonHDL ≥100 mg/dL | At 24 weeks, TG reduction was 49.8% with 10 mg quarterly: 56% with 25 mg quarterly: 62.4% with 50 mg quarterly, and 44.2% with 50 mg halfyearly. Worsening glycemic control more frequent. |
| SHASTA-4 Study[37] (phase 2b study) | Adults (≥18) with severe hypertriglyceridemia: documented fasting TG ≥500 mg/dL | Significant dose-dependent reduction in triglyceride levels by 57% and ApoCIII by 77% by 24 weeks. |
| PALISADE study[38] - 75 patients |
Adults with genetically confirmed or clinically diagnosed familial chylomicronemia syndrome (FCS) or persistent chylomicronemia with very high triglycerides | Median TG reductions 80% (25 mg) and 78% (50 mg) at 10 months; At 12 months: 78% (25 mg) and (50 mg). 83% reduction in risk of adjudicated acute pancreatitis events |
| MUIR3 study | Adults (≥18 years), with hypertriglyceridemia (HTG): TG 150-499 mg/dL | Ongoing trial |
TG: Triglycerides, Apo CIII: Apolipoprotein C-III, LDL-C: Low-density lipoprotein cholesterol, HDL: High-density lipoprotein
Plozasiran-key takeaway points
Plozasiran may be used for those with familial chylomicronemia syndrome and very high TG levels
Plozasiran may be used for adults with severe hypertriglyceridemia
Plozasiran may be used in mixed hyperlipidemia: TG 150–499 mg/dL with either LDL-C ≥70 mg/dL or nonHDL ≥100 mg/dL.
Recommendations for Plozasiran
Plozasiran is not yet approved by the FDA for familial chylomicronemia.
GUIDELINE RECOMMENDATION OF APO CIII INHIBITORS
The ESC 2025 guidelines recommend volanesorsen (300 mg/week) for severe hypertriglyceridemia (>750 mg) due to familial chylomicronemia syndrome (CLASS IIA, LEVEL B).[21]
ROLE OF NOVEL LLT DRUGS IN WOMEN
In women, serum cholesterol levels vary with age and tend to rise significantly after menopause, reaching higher levels over time than in men.[39] The rate of CV disease tends to rise in 7th decade in women. Despite later age of onset of ASCVD in women, women tend to have higher LDL at baseline.[40] In those with HoFH, total- and LDL-C levels are higher in girls than boys. By adulthood, women tend to have a higher LDL-C, are more likely to be underdiagnosed, and are less likely to receive lipid-lowering treatment than men. This leads to severe atherosclerotic CV disease risk in women.[41]
Women do not generally tolerate high-intensity statins due to a higher rate of myalgia compared to men.[42] Women are less likely to achieve guideline-recommended LDL-C targets driven by higher statin intolerance, lower high-intensity statin use, and smaller LDL-C reductions even on high-intensity therapy.[43] This could partly be driven by genetic polymorphisms in PCSK9 genes. The mutated G allele of rs505151 can lead to a higher cholesterol level in women while leading to a lower cholesterol level in men, thereby increasing the CV risk.[44] The resulting variability in LDL-C levels makes women more prone to ASCVD. In patients with familial chylomicronemia syndrome, there is marked elevation of TG levels and risk of pancreatitis. While chylomicronemia is more common in men, women tend to have increased risks during pregnancy.[45]
Thus, women represent a challenging group where there is both higher prevalence of dyslipidemia and ASCVD, while most of them tend to be under-treated or receive ineffective drugs. Inclisiran safety and efficacy are proven in par in women, and evidence is shown in Figure 7.[46,47]
- Inclisiran in women. (LDL: Low-density lipoprotein, Lp(a): Lipoprotein a)
In HoFH with refractory hyperlipidemia, evinacumab can be recommended as a third-line drug after high-dose statins (+ezetimibe and/bempedoic acid) and PCSK9 inhibitors.[41] In the ELIPSE HoFH trial, 56% were women, and evinacumab leads to a significant relative LDL reduction which was sustained over 24 weeks.[22] In another large cohort of patients with homozygous familial hypercholesterolemia, including 57 (49.1%) females, and in a study of 14 pediatric patients (5–11 years), with 57% females, evinacumab was found to be equally effective in women.[23,24]
In patients with severely elevated TG levels due to FCS, trials such as APPROACH trial (17/33 female)[29] and the BROADEN study (29/40 female)[32] demonstrated that volanesorsen was effective in reducing TG levels, but with the side effect of thrombocytopenia.
Olezarsen, another Apo CIII inhibitor was tested in patients with familial chylomicronemia syndrome in the BALANCE study, where 58% were female, the BRIDGE–TIMI 73a, where 42% were female, and the ESSENCE–TIMI 73b trial, included 40% females. Olezarsen was found to significantly reduce TG and Apo CIII levels, and no gender specific difference in effectiveness was reported.[33-35]
Thus, drugs such as inclisiran, ANGPTL3 inhibitors, and Apo CIII inhibitors, which can overcome the side effects of statins, may be more effective in women. Although most of the studies have reported equivalent effectiveness in women, lack of gender specific randomized control trials limits data on women-specific use of these drugs and information to address special challenges in managing dyslipidemia in women such as during pregnancy and breastfeeding.
CONCLUSION
Despite an alarming rise in heart disease and the known risks of LDL-C, statin usage remains low, particularly in low-middle-income countries (6.7%) and even in the U.S. (35%). Challenges persist due to patient-related issues such as non-compliance, lack of affordability, lack of availability, inadequate dosing, and side effects of drugs leading to intolerance and presence of genetic variants that make statins ineffective. Lack of data and special considerations like pregnancy make controlling lipids in women especially challenging. Research into different targets in the lipid cycle has produced new drug classes targeting LDL and other factors like TGs and Lp(a) that contribute to residual CV risk. In this review, three such novel groups of drugs have been reviewed. Their respective studies have clearly established their effectiveness in lowering cholesterol levels but clinical evidence to show their effectiveness in preventing CV disease is still emerging. In the future, further research may address this therapeutic gap in heart disease prevention and improve the CV outcomes of patients. There is also a need to perform women-focused randomized control trials to assist in managing dyslipidemia in women better.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
Patient’s consent is not required as there are no patients in this study.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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