What is the effect of inclisiran on elevated LDL cholesterol levels?

Effect of Inclisiran on Elevated LDL Cholesterol Levels

Inclisiran significantly reduces LDL cholesterol levels by approximately 50% through inhibition of PCSK9 production, offering an effective treatment option for patients with elevated LDL-C who require additional lipid-lowering beyond statins. 1

Mechanism of Action and Efficacy

• Inclisiran is a long-acting, synthetic small interfering RNA (siRNA) that selectively silences PCSK9 messenger RNA translation, inhibiting hepatic PCSK9 protein production and thereby up-regulating LDL receptor density on hepatocytes 1
• Unlike PCSK9 monoclonal antibodies that bind to the protein extracellularly, inclisiran works intracellularly to prevent PCSK9 production 1
• In phase 3 clinical trials (ORION-9, ORION-10, ORION-11), inclisiran demonstrated a mean placebo-corrected reduction in LDL-C of 50.7% at day 510 1
• The time-adjusted mean reduction in LDL-C was 50.5%, indicating sustained efficacy throughout the treatment period 1, 2
• In the ORION-10 trial, inclisiran reduced LDL-C levels by 52.3%, while in the ORION-11 trial, it reduced levels by 49.9% 2

Dosing and Administration

• The recommended dosage is 284 mg administered as a subcutaneous injection initially, again at 3 months, and then every 6 months thereafter 1, 3
• This infrequent dosing schedule (twice-yearly maintenance) offers a significant advantage for medication adherence compared to other non-statin therapies 4, 5
• Inclisiran is indicated as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic cardiovascular disease (ASCVD) who require additional LDL-C lowering 1, 3

Safety Profile

• Inclisiran has demonstrated a favorable safety profile in clinical trials, with most adverse events similar to placebo 1, 2
• The most common adverse reactions (occurring in ≥3% of patients) include injection site reactions, arthralgia, and bronchitis 3
• Injection site reactions were more frequent with inclisiran than placebo (2.6% vs. 0.9% in ORION-10 and 4.7% vs. 0.5% in ORION-11), but were generally mild and not persistent 2
• Serious adverse events occurred in 11% of patients receiving inclisiran compared to 8% in the placebo group in early trials 6
• No dose adjustments are necessary for patients with mild, moderate, or severe renal impairment or mild to moderate hepatic impairment 3

Cardiovascular Outcomes

• The effect of inclisiran on cardiovascular morbidity and mortality has not yet been definitively determined 1
• Two cardiovascular outcomes trials, ORION-4 and VICTORION-2P, are currently in progress to assess the impact of inclisiran on major adverse cardiovascular events 1
• In an exploratory analysis from the ORION trials, cardiovascular events occurred in 7.4% of the inclisiran group versus 10.2% of the placebo group in ORION-10, and 7.8% versus 10.3% in ORION-11 1
• A patient-level pooled analysis suggested that cardiovascular events were reduced with inclisiran versus placebo (7.1% vs. 9.4%) 7

Special Populations

• Inclisiran has shown consistent efficacy across different patient populations, including those with diabetes 1
• In the ORION-10 trial, 47.5% of patients in the inclisiran group had diabetes, while in ORION-11,36.5% had diabetes 1
• The safety and effectiveness of inclisiran have not been established in pediatric patients 3
• No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients 3

Clinical Considerations and Caveats

• Inclisiran is contraindicated in patients with prior serious hypersensitivity reactions to the drug or its excipients 3
• Serious hypersensitivity reactions, including angioedema, have been reported in post-marketing surveillance 3
• Unlike PCSK9 monoclonal antibodies, which have established cardiovascular outcome benefits, the definitive cardiovascular outcomes data for inclisiran are still pending 1
• The convenience of twice-yearly dosing may improve adherence compared to other lipid-lowering therapies that require more frequent administration 5, 7

Place in Therapy

• Inclisiran is recommended as an option for non-statin therapy in patients who cannot achieve LDL-C goals with maximally tolerated statin therapy 4
• It may be particularly valuable for patients who struggle with adherence to more frequently dosed medications 4, 5
• The American College of Cardiology and American Diabetes Association include inclisiran among non-statin LDL-lowering therapies that can be added when LDL-C goals are not met with statin therapy alone 1, 4