Leqvio Liver Function Impact: What Inclisiran Does (and Does Not Do) to Your Liver

Does inclisiran affect liver function?

Hepatotoxicity is not a warning in the Leqvio label. There is no boxed warning, and the single Warning and Precaution is hypersensitivity reactions [1]. The prescribing information does not call for routine liver-function testing before or during treatment; its dosing section asks for LDL-C to be assessed when clinically indicated [1].

The drug does its work in hepatocytes, so the sections below cover how it reaches the liver, how quickly it clears from plasma, and what the trials and label recorded.

How a drug that works in the liver reaches its target

Inclisiran is a double-stranded small interfering RNA conjugated on the sense strand to triantennary N-acetylgalactosamine (GalNAc), which helps hepatocytes take it up. Inside the hepatocyte it directs catalytic breakdown of PCSK9 messenger RNA. Less PCSK9 means more LDL receptor recycling and expression on the liver cell surface, so more LDL-C is taken up from the circulation [1]. The liver is the target organ for inclisiran's cholesterol-lowering action.

Plasma exposure is brief. After a 284 mg subcutaneous dose, concentrations peak at about 4 hours (mean Cmax 509 ng/mL) and are undetectable by 24 to 48 hours, with a terminal half-life of about 9 hours and no accumulation [1]. The label describes high uptake into, and selectivity for, the liver, and LDL-C lowering persists for months after a dose despite that short plasma half-life [1]. Inclisiran is broken down by nucleases into shorter nucleotides and is not a substrate for CYP450 enzymes or transporters [1].

This describes how inclisiran lowers LDL-C. The reported adverse reactions and warnings describe its known safety findings.

What the trials and the label recorded

ORION-10 enrolled 1,561 adults with atherosclerotic cardiovascular disease and ORION-11 enrolled 1,617 with ASCVD or an ASCVD risk equivalent, all on maximally tolerated statins. Patients received 284 mg or placebo on day 1, day 90, and every 6 months thereafter. The placebo-corrected LDL-C change at day 510 was -52% in ORION-10 and -50% in ORION-11, and adverse events were generally similar to placebo except for more injection-site events [2].

The label's pooled safety table covers 1,833 adults on Leqvio (1,682 exposed for 18 months, median 77 weeks) against 1,822 on placebo. Injection site reaction occurred in 8% versus 2%, arthralgia in 5% versus 4%, and bronchitis in 4% versus 3%. Adverse reactions led to discontinuation in 2.5% versus 1.9%, most often injection-site reactions (0.2% versus 0%) [1]. The table lists reactions occurring in at least 3% of Leqvio-treated patients and more often than with placebo. The postmarketing list consists of hypersensitivity reactions: anaphylaxis, angioedema, rash, pruritus and urticaria [1].

The phase 1 trial in healthy volunteers with LDL cholesterol of at least 100 mg/dL was small, with four to eight participants per dose cohort. Participants received single doses of 25 to 800 mg or multiple-dose regimens. All adverse events were mild or moderate, with no serious adverse events and no discontinuations for adverse events. There was one grade 3 elevation in gamma-glutamyltransferase, which the investigator considered related to statin therapy [3].

What about people who already have liver disease?

The label makes no dose adjustment for mild to moderate hepatic impairment and states that inclisiran has not been studied in severe hepatic impairment [1]. Exposure does rise with liver disease: mild to moderate impairment increased Cmax 1.1- to 2.1-fold and AUC 1.3- to 2.0-fold [1]. In moderate impairment, baseline PCSK9 was lower and LDL-C reductions were smaller than in people with normal liver function [1].

Does inclisiran interact with other drugs through the liver?

No formal clinical drug interaction studies were conducted with inclisiran [1]. The label states that it is not a substrate, inhibitor or inducer of cytochrome P450 enzymes or transporters and is not expected to cause or be affected by CYP or transporter interactions [1]. In a population pharmacokinetic analysis it did not clinically significantly change atorvastatin or rosuvastatin concentrations, and the label lists no specific interacting drug [1].

What the label does say to watch for

Hypersensitivity is the one Warning and Precaution in the label. Anaphylaxis and angioedema have been reported with Leqvio, and postmarketing reports add rash, pruritus and urticaria [1]. The label advises patients on the signs and symptoms and instructs them to seek medical attention promptly [1]. A prior serious hypersensitivity reaction to inclisiran or any excipient in Leqvio is a contraindication [1].

What is not known

Severe hepatic impairment was not studied [1]. The pooled adult safety data include a median of 77 weeks of exposure [1].