What is the role of Inclisiran (RNA interference therapeutic) in managing primary hypercholesterolemia or mixed dyslipidemia?

From the Guidelines

Inclisiran is a highly effective RNA interference therapeutic for managing primary hypercholesterolemia or mixed dyslipidemia in patients who cannot achieve target LDL-C levels with maximally tolerated statins, with a recommended dosing regimen of 284 mg administered as a subcutaneous injection initially, again at 3 months, and then every 6 months thereafter. This convenient twice-yearly maintenance dosing schedule offers a significant advantage over other lipid-lowering therapies that require more frequent administration. Inclisiran works by inhibiting PCSK9 protein production in the liver, which increases LDL receptor availability and enhances LDL cholesterol clearance from the bloodstream 1.

Key Benefits of Inclisiran

• Inclisiran typically reduces LDL-C levels by approximately 50-55% when added to statin therapy, with effects sustained throughout the dosing interval 1.
• Common side effects include injection site reactions such as pain, redness, or rash, but these are generally mild and transient 1.
• Inclisiran is particularly valuable for patients with atherosclerotic cardiovascular disease, familial hypercholesterolemia, or those who are statin-intolerant 1.
• Unlike monoclonal antibodies that target PCSK9, inclisiran's mechanism at the RNA level results in more durable LDL-C reduction with less frequent dosing 1.

Clinical Considerations

• The use of inclisiran may be considered in patients with demonstrated poor adherence to PCSK9 mAbs or those who may be unable to self-inject 1.
• There is currently no evidence or mechanistic plausibility for additional efficacy in LDL-C lowering or cardiovascular outcomes benefit for combination therapy with a PSCK9 mAb and inclisiran when added to maximally tolerated statin therapy with or without ezetimibe or bempedoic acid; therefore, if inclisiran is to be used, it should be in place of a PCSK9 mAb 1.
• Inclisiran has been approved for the treatment of FH by the FDA based upon its demonstrated efficacy in lowering LDL-C but does not yet have outcomes data 1.
• The ORION-4 and VICTORION-2P cardiovascular outcomes trials with inclisiran are currently in progress and are anticipated to be completed in 2026 and 2027, respectively 1.

Recent Guidelines and Recommendations

• The 2024 recommendations on the optimal use of lipid-lowering therapy in established atherosclerotic cardiovascular disease and following acute coronary syndromes suggest that inclisiran may be considered as an option in the process of shared decision-making regarding nonstatin therapies 1.
• In the UK, a commercial agreement has existed since 2021 between the manufacturer of inclisiran and the National Health Service (NHS), and inclisiran is recommended as an option in treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia in patients with a history of cardiovascular events when LDL-C is > 100 mg/dL (2.6 mmol/L) despite maximally tolerated statin therapy or in combination with other LLTs when statins are not tolerated or are contraindicated 1.

From the FDA Drug Label

LEQVIO is a small interfering RNA (siRNA) directed to proprotein convertase subtilisin kexin type 9 (PCSK9) mRNA indicated as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce low-density lipoprotein cholesterol (LDL-C). Inclisiran is a double-stranded small interfering ribonucleic acid (siRNA), conjugated on the sense strand with triantennary N-Acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes. In hepatocytes, inclisiran utilizes the RNA interference mechanism and directs catalytic breakdown of mRNA for PCSK9 This increases LDL-C receptor recycling and expression on the hepatocyte cell surface, which increases LDL-C uptake and lowers LDL-C levels in the circulation.

The role of Inclisiran in managing primary hypercholesterolemia or mixed dyslipidemia is as an adjunct to diet and statin therapy to reduce low-density lipoprotein cholesterol (LDL-C) levels. Inclisiran works by utilizing the RNA interference mechanism to direct the catalytic breakdown of PCSK9 mRNA, leading to increased LDL-C receptor recycling and expression on the hepatocyte cell surface, resulting in increased LDL-C uptake and lowered LDL-C levels in the circulation 2.

Key points:

• Inclisiran is indicated for the treatment of adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH).
• It is used as an adjunct to diet and statin therapy to reduce LDL-C levels.
• Inclisiran utilizes the RNA interference mechanism to direct the catalytic breakdown of PCSK9 mRNA.
• This leads to increased LDL-C receptor recycling and expression on the hepatocyte cell surface, resulting in increased LDL-C uptake and lowered LDL-C levels in the circulation.

From the Research

Role of Inclisiran in Managing Primary Hypercholesterolemia or Mixed Dyslipidemia

Inclisiran is a small interfering RNA (siRNA) therapeutic that plays a significant role in managing primary hypercholesterolemia or mixed dyslipidemia by preventing the hepatic synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9), thereby decreasing circulating low-density lipoprotein cholesterol (LDL-C) levels 3.

Mechanism of Action and Indications

• Inclisiran is administered subcutaneously and is indicated in adults with primary hypercholesterolemia or mixed dyslipidemia, as an adjunct to diet, for use in patients unable to reach LDL-C goals on maximally tolerated statin therapy, with or without other lipid-lowering therapies (LLTs) 3.
• It can be used with or without other LLTs in patients who are statin intolerant or for whom a statin is contraindicated 3.

Efficacy in Clinical Trials

• Clinical trials have shown that twice-yearly injections of inclisiran approximately halved LDL-C levels in patients with, or at high risk of developing, atherosclerotic cardiovascular disease (ASCVD) who had hypercholesterolemia, irrespective of whether or not their existing treatment included a statin 3, 4, 5.
• A pooled patient-level analysis of inclisiran trials in patients with familial hypercholesterolemia or atherosclerosis demonstrated that inclisiran reduced LDL-C levels by approximately 50% compared to placebo, with a similar safety profile 4.

Safety and Tolerability

• The safety and tolerability profile of inclisiran was similar to placebo, although mild to moderate, transient injection-site adverse reactions were more frequent with inclisiran 3, 4, 5.
• Liver and kidney function tests, creatine kinase values, and platelet counts did not differ between groups 4.

Clinical Potential

• Inclisiran has the potential to overcome the gap between guideline recommendations and real-world clinical practice in current LDL-C-lowering therapies, with a focus on reduced LDL-C level variability and improved treatment adherence 6.
• Its administration by biannual injection is expected to greatly improve treatment adherence, and ongoing studies accumulate evidence of its longer-term safety 6.