Leqvio Cognitive Function Impact: What the Evidence Actually Shows

Does inclisiran affect memory or thinking?

The Leqvio prescribing information does not describe a cognitive effect. The label's Warnings and Precautions section contains one entry, hypersensitivity reactions including anaphylaxis and angioedema, and its table of common adverse reactions lists three events: injection site reaction, arthralgia and bronchitis [2]. Memory, confusion, attention and word-finding are not among them.

Inclisiran is not a statin. It is a small interfering RNA that directs breakdown of PCSK9 messenger RNA in liver cells, which increases LDL receptor recycling and lowers circulating LDL-C [2].

What ORION-10 and ORION-11 measured

ORION-10 randomized 1,561 adults with atherosclerotic cardiovascular disease; ORION-11 randomized 1,617 adults with ASCVD or a risk equivalent. Everyone was on a maximally tolerated statin with LDL-C still elevated, and mean baseline LDL-C was about 105 mg/dL in both trials [3].

Inclisiran 284 mg was given on day 1, day 90 and then every 6 months for 540 days. The two primary endpoints in each trial were the placebo-corrected percentage change in LDL-C at day 510 and the time-adjusted percentage change from day 90 to day 540, both lipid measurements [3]. In the published report, inclisiran lowered LDL-C by 52.3% in ORION-10 and 49.9% in ORION-11 at day 510 [3].

Adverse events across the two trials were generally similar to placebo except for more injection site events [3]. That is a general statement about tolerability, not a finding about memory.

What the Leqvio label lists

The label pools three placebo-controlled trials: 1,833 adults treated with Leqvio, 1,682 of them exposed for 18 months (median 77 weeks), against 1,822 on placebo [2]. Table 1 gives the reactions reported in at least 3% of Leqvio patients and more often than with placebo:

• Injection site reaction: 8% on Leqvio vs 2% on placebo (pain, erythema, rash)
• Arthralgia: 5% vs 4%
• Bronchitis: 4% vs 3%

Adverse reactions led to discontinuation in 2.5% of Leqvio patients and 1.9% of placebo patients, most often injection site reactions (0.2% vs 0%) [2].

Inclisiran is conjugated to triantennary N-acetylgalactosamine to help hepatocytes take it up, and the label notes high uptake into, and selectivity for, the liver, the target organ for cholesterol lowering [2].

The one serious risk in the Warnings and Precautions section is hypersensitivity, including anaphylaxis and angioedema. The label says patients should be instructed to seek medical attention promptly for signs of it, and it lists a prior serious hypersensitivity reaction to inclisiran or its excipients as a contraindication [2].

Headache in the adolescent HeFH trial

In the 12-month double-blind part of the pediatric HeFH trial, 141 patients aged 12 and older, 93 on Leqvio and 48 on placebo, the safety profile matched adults except for headache, which occurred in 13% of Leqvio patients and 6% of placebo patients [2]. Headache is not a measure of memory or thinking, and the label reports it only as a headache difference [2].