Inclisiran
Overview
Inclisiran is a small interfering RNA therapy that lowers low-density lipoprotein cholesterol by reducing production of proprotein convertase subtilisin/kexin type 9, commonly known as PCSK9, in the liver. The molecule is conjugated with N-acetylgalactosamine to facilitate uptake by hepatocytes, where it directs degradation of PCSK9 messenger RNA. Reduced PCSK9 production increases recycling and expression of LDL receptors on the surface of liver cells, allowing greater removal of LDL cholesterol from the bloodstream. Inclisiran is administered by subcutaneous injection and provides prolonged LDL-C reduction with an infrequent maintenance dosing schedule. It is used as an adjunct to diet and exercise and may be used with other lipid-lowering therapies depending on the patient's treatment requirements. Its mechanism differs from monoclonal antibody PCSK9 inhibitors because it acts at the RNA level to reduce hepatic PCSK9 production rather than directly binding circulating PCSK9 protein.
Background and Date of Approval
Inclisiran was developed as a first-in-class PCSK9-directed small interfering RNA therapy for sustained reduction of LDL cholesterol. The European Medicines Agency granted marketing authorisation for Leqvio on December 9, 2020 for adults with primary hypercholesterolaemia, including heterozygous familial and non-familial disease, or mixed dyslipidaemia. The United States Food and Drug Administration approved inclisiran on December 22, 2021 as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolaemia or clinical atherosclerotic cardiovascular disease requiring additional LDL-C lowering. The U.S. indication was subsequently revised in July 2025 to cover adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia, as an adjunct to diet and exercise. On February 12, 2026, the FDA also approved inclisiran for pediatric patients aged 12 years and older with homozygous familial hypercholesterolemia. The ORION clinical development program provided the principal clinical evidence for LDL-C reduction and long-term treatment effects.
Uses
Inclisiran is indicated to reduce LDL cholesterol in adults with hypercholesterolemia and in adults and pediatric patients aged 12 years and older with heterozygous familial hypercholesterolemia. It is also indicated in pediatric patients aged 12 years and older with homozygous familial hypercholesterolemia. Depending on the applicable indication and treatment plan, it may be used with statins or other lipid-lowering therapies.
Administration
Inclisiran is administered as a 284 mg subcutaneous injection by a healthcare professional. The initial dose is followed by a second dose three months later and then maintenance doses every six months. The injection may be administered into the abdomen, upper arm, or thigh. LDL-C levels may be assessed when clinically indicated to evaluate treatment response and guide overall lipid management.
Side Effects
Common side effects include injection-site reactions such as pain, redness, or rash. Other reported adverse effects include joint pain, bronchitis, urinary tract infection, diarrhea, pain in an extremity, and difficulty breathing. Injection-site reactions are generally localized and transient, although their severity can vary among patients.
Warnings
Serious hypersensitivity reactions, including angioedema, can occur and represent an important contraindication in patients with a previous serious hypersensitivity reaction to inclisiran or its excipients. Severe or persistent allergic symptoms require prompt medical evaluation and discontinuation where clinically appropriate. Long-term cardiovascular outcome effects should be interpreted within the evidence available for the approved population, as LDL-C lowering does not by itself establish an identical outcome benefit for every patient group.
Precautions
Patients should have their lipid profile and overall cardiovascular risk assessed before treatment and periodically thereafter. Inclisiran is not a substitute for dietary management or appropriate background lipid-lowering therapy when these are indicated. Hypersensitivity history should be reviewed before administration. Clinically significant classical drug-drug interactions are not a major feature of inclisiran because it is an siRNA therapy rather than a conventional small-molecule drug metabolized through common hepatic enzyme pathways. Treatment in pregnancy should be considered according to the clinical circumstances because available human pregnancy data are limited.
Expert Tips
Inclisiran is particularly useful when substantial and sustained LDL-C reduction is required and an infrequent administration schedule may support treatment adherence. Confirming the appropriate hypercholesterolemia or familial hypercholesterolemia diagnosis and assessing the patient's overall cardiovascular risk are important before initiation. LDL-C should be monitored according to the patient's clinical needs, while injection sites should be observed for local reactions. Healthcare professionals should administer the injection and counsel patients about the importance of continuing prescribed diet and other lipid-lowering therapies. Coordination with cardiology, lipid specialists, or primary care clinicians can help integrate inclisiran into long-term cardiovascular risk management.