PCSK9 inhibitors are agents that inhibit Proprotein Convertase Subtilisin/Kexin Type 9, an enzyme that plays an important role in the degradation of low-density lipoprotein receptors . By inhibiting this enzyme, these agents favor low-density lipoprotein catabolism and reduce plasma low-density lipoprotein cholesterol levels .

The optimal achieved low-density lipoprotein cholesterol level for long-term efficacy and safety remains unknown . Furthermore, the effect of adding the PCSK9 inhibitor alirocumab to statin therapy on coronary plaque burden and composition remains largely unknown .

Prevention & Lipids

PCSK9 inhibitors

PCSK9i efficacy, outcomes, and cost-effectiveness

Also called PCSK9i, evolocumab, alirocumab

Sources: 4 landmark trials · 12 new papers · 5 key papers · updated Oct 20, 2026

Overview

Unverified · drafted by AI from the sources cited below

Definition

PCSK9 inhibitors are agents that inhibit Proprotein Convertase Subtilisin/Kexin Type 9, an enzyme that plays an important role in the degradation of low-density lipoprotein receptors.1

Treatment

Evolocumab, a PCSK9 inhibitor, significantly reduced low-density lipoprotein cholesterol by a mean difference of -57.73 mg/dL in a meta-analysis of 67,662 patients.1 In the FOURIER trial, 27 564 patients with atherosclerotic cardiovascular disease received evolocumab or placebo, with 6635 patients subsequently enrolling in an open-label extension.2 Another PCSK9 inhibitor, alirocumab, was evaluated at a dose of 150 mg in 300 patients with acute myocardial infarction.3 Investigational oral PCSK9 inhibitors have also been evaluated in trials including 949 participants.4 Additionally, in vivo CRISPR base-editing technologies are being investigated in ongoing clinical trials as a strategy to permanently reduce circulating PCSK9 levels following a single infusion.5

Open questions

The optimal achieved low-density lipoprotein cholesterol level for long-term efficacy and safety remains unknown.1 Furthermore, the effect of adding the PCSK9 inhibitor alirocumab to statin therapy on coronary plaque burden and composition remains largely unknown.2

Landmark trials

Primary results of 4 trials behind the evidence on pcsk9 inhibitors, as each trial’s own publication reports them.

Left of the line at 1 favours the intervention; square size tracks trial size.Favours the interventionNo significant differenceFavours the comparator

0.512

ODYSSEY OUTCOMES
alirocumab vs placebo · 18,924 patients · N Engl J Med 2018
In patients who had an acute coronary syndrome 1 to 12 months earlier
Primary outcome: a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization
HR 0.85 (0.78–0.93)
FOURIER
evolocumab vs placebo · 27,564 patients · N Engl J Med 2017
In patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy
Primary outcome: the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization
HR 0.85 (0.79–0.92)

Reported as a difference or win ratio

ORION-10day 510 placebo-corrected % change
inclisiran vs placebo · 1,561 patients · N Engl J Med 2020
Primary outcome: the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510
“by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial”
ORION-10time-adjusted % change after day 90 up to day 540
inclisiran vs placebo · 1,561 patients · N Engl J Med 2020
Primary outcome: the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540
“time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2)”
ORION-11day 510 placebo-corrected % change
inclisiran vs placebo · 1,617 patients · N Engl J Med 2020
Primary outcome: the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510

Results are quoted from each trial’s primary publication abstract (PubMed); the trial name links to the paper. Ratios below 1 favour the intervention.

Key papers

Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction

JAMA — Räber L

616 citations · 2022 · among the most cited on PCSK9 inhibitors

Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease

Circulation — O’Donoghue M

410 citations · 2022 · among the most cited on PCSK9 inhibitors

Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE

Circulation — Gaba P

186 citations · 2023 · among the most cited on PCSK9 inhibitors

Association of lipid-lowering drugs with COVID-19 outcomes from a Mendelian randomization study

eLife

164 citations · 2021 · among the most cited on PCSK9 inhibitors

A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors

Journal of Medicinal Chemistry — Tucker T

160 citations · 2021 · among the most cited on PCSK9 inhibitors

How this page is built

A clinical question appears here only when its condition matches this topic, an outcome and a comparator were extracted from the studies, at least two studies and a patient count are on file, and the certainty is low or higher.

Supports benefit, no benefit shown, and mixed describe the direction of the measured effect. No benefit shown means the evidence does not support a benefit. It is not a finding of harm. Too little evidence means the question did not clear that bar.

Study count, RCT count, and patient count are separate. The patient total adds only studies that are linked into a study family and whose sample size is not flagged as implausible. A reversal is listed only when at least one randomized trial sits on each side of the change.

The overview is drafted from the guideline recommendations, trials, papers, and questions on this page, and every sentence has to cite one of them. It stays unverified until an NPI-verified clinician or a Synapse admin approves it. Approving records that person's name.

ORION-11time-adjusted % change after day 90 up to day 540

inclisiran vs placebo · 1,617 patients · N Engl J Med 2020

Primary outcome: the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540

“and 49.2% (95% CI, 46.8 to 51.6)”