Clinical Overview: Inclisiran for Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease

Inclisiran (Leqvio) is a small interfering ribonucleic acid approved by the FDA for patients who are on a maximally-tolerated dose of statins and need additional LDL-C reduction.

High levels of low-density lipoprotein cholesterol (LDL-C) due to genetic factors or lifestyle choices are a major risk factor for atherosclerotic cardiovascular disease (ASCVD).1 Although statins are effective in reducing LDL-C, patients with heterozygous familial hypercholesterolemia (HeFH) or who are at high risk for ASCVD may require additional reduction of LDL-C.2

Inclisiran (Leqvio) is a small interfering ribonucleic acid (siRNA) approved by the FDA in December 2021 for patients who are on a maximally-tolerated dose of statins and need additional LDL-C reduction.2 Three double-blind, randomized, placebo-controlled clinical trials demonstrated inclisiran’s efficacy in 3457 patients with ASCVD or HeFH on maximally-tolerated statin therapy.

The researchers found that inclisiran reduced the LDL-C by 48%-52%, total cholesterol by 30%-33%, non-HDL-C by 42%-47%, and apoprotein B by 36%-43% from baseline in these 3 studies.2

Mechanism of action

Circulating plasma LDL-C binds to LDL receptors on hepatocytes and undergoes internalization by receptor-mediated endocytosis. LDL is degraded in the liver and LDL receptors are recycled to the hepatocyte surface to repeat the cycle.

Proprotein convertase subtilisin kexin type 9 (PCSK9; a plasma protease synthesized in liver) binds to LDL receptors associated with LDL-C. When this complex undergoes internalization, hepatic lysosomal enzymes destroy the entire complex.

Thus, LDL receptor recycling and plasma LDL clearance is reduced, leading to increased plasma LDL-C.3,4 Inclisiran activates the RNA-silencing complex in hepatocytes to destroy PCSK9 messenger RNA (mRNA) and reduces plasma PCSK9 levels. More LDL receptors are thereby recycled, leading to increased plasma LDL-C clearance.5

Dosage and administration2

Inclisiran is supplied in a single-dose prefilled syringe containing 1.5 ml of clear and colorless to pale-yellow solution at pH 7.0 with 284 mg of the drug. Health care professionals should store inclisiran between 20-25 degrees C (68-77 degrees F) and administer inclisiran to patients subcutaneously in the abdomen, upper arm, or thigh.

They should administer the second dose 3 months after the first dose and then 1 dose every 6 months. If the patient misses a dose, health care professionals must determine the time elapsed since the planned dose. If fewer than 3 months have elapsed, they should administer the dose and continue with the patient’s original schedule; otherwise, the patient must restart a new regimen.

Adverse events (AEs)2

The most common AEs experienced by patients on inclisiran are injection site reactions (pain, erythema, and rash). Other AEs reported with greater frequency than placebo during clinical trials were arthralgia, urinary tract infections, diarrhea, bronchitis, and dyspnea.

Warnings/precautions2

There are no contraindications to inclisiran. Dosage reductions are not required for patients with mild to moderate hepatic dysfunction, those with mild to severe renal dysfunction, or for geriatric patients. Inclisiran has not been studied in severe hepatic impairment. No drug interactions occur with inclisiran as it is metabolized by nucleases.

Health care professionals should avoid administering inclisiran in infected or injured areas of skin. They should discard inclisiran if they observe particulate matter or discoloration.

Pregnancy and Lactation2

Although inclisiran crosses the placenta and into milk in rats and rabbits, researchers have not seen developmental defects or teratogenicity during animal testing. Significant absorption of inclisiran by the breastfed infant is unlikely.

However, prescribers should discontinue inclisiran during pregnancy to prevent fetal harm due to reduced cholesterol and cholesterol-derived biologically active substances. Prescribers should weigh benefits of breastfeeding against the mother’s need for inclisiran.

About the Author

Alok Sharma is a professor of Pharmaceutical Sciences at Massachusetts College of Pharmacy and Health Sciences in Manchester, NH.

References

1. About heart disease and bad cholesterol (LDL-C). Accessed May 4, 2022. https://www.leqvio.com/about-bad-cholesterol

2. LEQVIO full prescribing information. December 2021. Accessed May 4, 2022. https://www.novartis.us/sites/www.novartis.us/files/leqvio.pdf

3. Handelsman Y, Lepor NE. PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review. J Am Heart Assoc. 2018;7(13):e008953. Published 2018 Jun 22. doi:10.1161/JAHA.118.008953

4. Peterson AS, Fong, LG, Young SG. PCSK9 Function and Physiology. J Lipid Res. 2008 Jun; 49(6): 1152–1156. doi: 10.1194/jlr.E800008-JLR200

5. Klinovski M, Boucher M, Perras C, Grobelna A. Inclisiran: A Small Interfering RNA Molecule for Treating Hypercholesterolemia. In: CADTH Issues in Emerging Health Technologies. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; December 1, 2019.1-13.