# Pleiotropy of PCSK9 Inhibition

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $339,965

## Abstract

ABSTRACT
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is new drug target to lower low-density lipoprotein
cholesterol (LDL) and prevent coronary heart disease (CHD). PCSK9 inhibitor drugs lower LDL levels
markedly – to below 25 mg/dL in 37% of patients – and show promise for CHD prevention. However, PCSK9
is widely expressed in many tissues and has biological effects beyond lowering LDL. For example, PCSK9
decreases the clearance of lipopolysaccharide (LPS); reduced PCSK9 function is associated with improved
survival from sepsis in animal models and humans. Additionally, PCSK9 has effects on bone, pancreas, brain
and nerve tissues, among others. The benefits and risks from inhibiting the pleiotropic effects of PCSK9 and
from long-term exposure to extremely low LDL levels are not known, but clinical trials have already raised
concerns about effects on cognitive function. Thus, the recent approval of the first of many PCSK9 inhibitors in
development has exposed critical knowledge gaps: we do not know the potential long-term beneficial and
deleterious effects of 1) PCSK9 inhibition, or 2) extremely low LDL levels. Traditional post-marketing drug-
safety approaches to these questions would require decades of clinical studies to determine these long-term
effects. We hypothesize that the unknown beneficial and deleterious effects of long-term PCSK9 inhibition can
be defined by studying individuals with genetically determined (and therefore lifetime exposure) variation in
PCSK9 activity. Similarly, the unknown risks and benefits of very low LDL levels can be defined by studying
individuals who have extremely low LDL levels unrelated to drug exposure. We will use BioVU, a database with
in depth genotyping linked to the de-identified electronic EHR in > 100,000 individuals at Vanderbilt to define
the potential risks and benefits of both PCSK9 inhibition and extremely low LDL levels. In Aim 1 we will test the
hypothesis that individuals with genetically determined low PCSK9 function have a lower risk of progressing
from infection to severe sepsis and septic shock. In Aim 2 we will use a combination of unbiased phenotype
identification (phenome-wide association scan or PheWAS) followed by rigorous validation of identified
phenotypes to test the hypothesis that PCSK9 variants associated with reduced function are associated with
clinical outcomes other than lower LDL. Aim 3 will use the same approach as Aim 2 to define the clinical
outcomes associated with very low LDL concentrations in the entire de-identified set of electronic health
records at Vanderbilt University Medical Center consisting of >2,500,000 patients of whom >246,000 have had
an LDL level measured. This proposal uses novel approaches to rapidly provide critical information about the
clinical consequences of both long-term PCSK9 inhibition and long-term low LDL levels that would otherwise
not be obtained without many years of patient exposure to PCSK9 drugs.

## Key facts

- **NIH application ID:** 9948684
- **Project number:** 5R01GM120523-05
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Qiping Feng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $339,965
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948684

## Citation

> US National Institutes of Health, RePORTER application 9948684, Pleiotropy of PCSK9 Inhibition (5R01GM120523-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9948684. Licensed CC0.

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