Genetic Validation for New LDL Cholesterol-Lowering Target

Megan Brooks

April 01, 2019

A new study confirms the mechanism by which ATP citrate lyase inhibition lowers plasma low-density-lipoprotein cholesterol (LDL-C) levels and provides genetic validation for this as a target for cardiovascular risk reduction.

The study indicates that ATP citrate lyase inhibitors lower LDL-C by the same mechanism of action as statins, and genetic variants associated with lower plasma LDL-C in the ATP citrate lyase gene are associated with a lower risk for cardiovascular events.

The study was published online March 14 in the New England Journal of Medicine.

ATP citrate lyase is an enzyme in the cholesterol–biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl–coenzyme A reductase (HMGCR), the target of statins. Whether genetic inhibition of ATP citrate lyase has the same effect (per unit decrease in LDL-C) as genetic inhibition of HMGCR is unclear, note the researchers, led by Brian A. Ference, MD, from the Centre for Naturally Randomized Trials, University of Cambridge, United Kingdom.

To investigate, they analyzed data on 654,783 individuals who experienced a total of 105,429 major cardiovascular events. They created genetic scores made up of inherited variants in the gene encoding ATP citrate lyase (ACLY) that mimic the effect of an ATP citrate lyase inhibitor and variants in HMGCR that mimic the effect of a statin.

They found that variants in ACLY and HMGCR were associated with similar patterns of changes in the concentration and lipid composition of plasma lipoproteins and had a "nearly identical" effect on the risk for cardiovascular events per decrease of 10 mg/dL in the LDL-C level, with odds ratios for ACLY of 0.823 (95% confidence interval [CI], 0.78 - 0.87; P = 4.0×10−14) and for HMGCR of 0.836 (95% CI, 0.81 - 0.87; P = 3.9×10−19).

This finding provides genetic validation of recent clinical evidence that lowering plasma LDL-C with an ATP citrate lyase inhibitor should provide cardiovascular risk reduction on par with inhibiting HMG-CoA with a statin for the same reduction in LDL-C, Ference and colleagues say.

The researchers speculate in their report that treatment with an ACLY inhibitor, whether used alone or in combination with a statin or ezetimibe, "would likely reduce the risk of cardiovascular events by approximately 20% for each decrease of 39 mg/dL (1.0 mmol/L) in the LDL cholesterol level."

Off-Target Effects?

This genetic study, they note, also provides biologic context for interpreting the results of the CLEAR Harmony trial of bempedoic acid, an ACLY inhibitor currently in development by Esperion Therapeutics.

In randomized controlled trials lasting roughly 12 weeks, bempedoic acid reduced LDL-C levels by up to 30% when used alone and by up to 50% in combination with ezetimibe.

In CLEAR Harmony, published as a companion report in the New England Journal of Medicine, the difference between bempedoic acid and placebo at 12 weeks with respect to the change from baseline in the LDL-C level was 18.1 percentage points in patients who were already receiving high- or moderate-intensity statin therapy.

In a linked editorial, Michael V. Holmes, MD, PhD, University of Oxford, United Kingdom, cautions that genetic associations for ACLY speak only to "target-mediated effects of ACL inhibition. Bempedoic acid may have off-target effects (i.e., effects not mediated through ACL inhibition), which would not be quantifiable in studies of human genetics."

Of note, in CLEAR Harmony, bempedoic acid was associated with decreased risk for new-onset or worsening diabetes (bempedoic acid vs placebo, 0.61; 95% CI, 0.41 - 0.92), a finding that "potentially supports the presence of target-mediated pleiotropic effects," Holmes notes.

Another bempedoic acid study, CLEAR WISDOM, presented at the recent American College of Cardiology 68th Annual Scientific Session, showed that treatment significantly lowered LDL cholesterol when added to maximally tolerated statins in high-CV-risk patients.

Patients treated with the investigational oral agent had a 15.1% reduction in the primary end point of LDL cholesterol at 12 weeks compared with a 2.4% increase for placebo (17.4% placebo-corrected difference; P < .001). Oral bempedoic acid also significantly reduced non-HDL cholesterol, total cholesterol, apolipoprotein B, and C-reactive protein levels.

Although not an outcomes trial, 1-year results showed a 2% reduction in adjudicated cardiovascular death, nonfatal MI, and nonfatal stroke events with bempedoic acid, compared with placebo (2.7% vs 4.7%). The 2% difference persisted when the composite end point also included coronary revascularization (5.7% vs 7.8%) and hospitalization for unstable angina (6.1% vs 8.2%).

An ongoing phase 3 cardiovascular outcome trial, CLEAR Outcomes, will provide additional information.

"More broadly, with unprecedented availability of open-access biobanks that are linked to electronic medical records and genomewide genotyping and emerging phenotyping (e.g., proteomics and metabolomics), the genetic characterization of drug targets is set to revolutionize how we develop medicines," Holmes writes.

Esperion Therapeutics funded the genetic study and the CLEAR Harmony study. Disclosures for authors are available at NEJM.org

N Engl J Med. 2019;380:1022-1032, 1033-1042, 1076-1079. CLEAR Harmony abstract, Ference full text, Editorial

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