Inhibition of enzyme upstream of statin target also lowers LDL-c levels and CV event risk
Mendelian Randomization Study of ACLY and Cardiovascular Disease
Introduction and methods
The enzyme ATP citrate lyase acts upstream of 3-hydroxy-3-methylglutaryl– coenzyme A reductase (HMGCR) in the cholesterol-biosynthesis pathway . It was anticipated that inhibiting ATP citrate lyase lowers LDL-c, but it is unclear whether it has the same CV reducing effect as inhibition of HMGCR with a statin.
The oral inhibitor of ATP citrate lyase bempedoic acid has indeed been shown to lower LDL-c levels by up to ~30% and up to ~50% in combination with ezetimibe in studies lasting 12 weeks [2-4]. In patients already on high- or moderate-intensity statin treatment, bempedoic acid lowered LDL-c by 18.1 percentage points from baseline to week 12, compared to placebo, according to the CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) Harmony trial . Incidence of CV events was reduced in patients treated with bempedoic acid, but higher rates of death due to CV disease and cancer were observed, compared to placebo. This finding raises the question whether inhibition of ATP citrate lyase is harmful.
This mendelian randomization study aimed to estimate the clinical effect of reducing LDL-c levels through inhibition of ATP citrate lyase, by comparing variants in the ACLY gene that mimic the effect of an ATP citrate lyase inhibitor with variants in the HMGCR gene that mimic the effect of a statin. Also, this study evaluated the effect of ACLY variants combined with variants in HMGCR and NPC1L1 (Niemann–Pick C1–like 1), which encode the proteins targeted by statins and ezetimibe, respectively.
Various data sources were used; individual data from 470.478 participants enrolled in the U.K. Biobank study, the Database of Genotypes and Phenotypes program of the National Center for Biotechnology Information, or in CARDIoGRAMplusC4D studies, and summary-level data of 184.305 participants included in the DIAGRAM consortium. The ACLY and HMGCR genetic scores were based on variants within the respective genes that are associated with reduced plasma LDL-c levels. The primary efficacy outcome was major CV events (composite of the first occurrence of myocardial infarction [MI], coronary revascularization, ischemic stroke, or coronary death). The primary safety outcome was any type of cancer.
- A 1-unit increase in the ACLY score was associated with an inverse-variance-weighted mean reduction in plasma LDL-c by 1.21 mg/dL (95%CI: 0.94-1.48, P=1.6x10^-18, 0.03 mmol/L, 95%CI: 0.02-0.04) and a decrease in plasma apoB levels of 1.00 mg/dL (95%CI: 0.77-1.23, P=7.2x10^-17).
- In participants with known lipid traits, the ACLY and HMGCR scores were associated with comparable patterns of changes in levels and lipid composition of plasma lipoproteins.
Association of genetic scores with CV events
- Per 10 mg/dL decrease in LDL-c, the ACLYscore was linked to 17.7% lower risk of major CV events (OR: 0.82, 95%CI: 0.78-0.87, P=4.0x10^-14) and 19.4% lower MI risk (OR: 0.81, 95%CI: 0.76-0.86, P=6.4x10^-12). The HMGCR score yielded a similar association with risk of major CV events (OR: 0.84, 95%CI: 0.82-0.87, P=3.9x10^-19) and risk of MI (OR: 0.83, 95%CI: 0.79-0.87, P=2.6x10^-14).
- The ACLY and HMGCR scores were associated with multiple different composite CV outcomes to a similar extent, and their individual components.
- For each 10 mg/dL decrease in LDL-c levels the NPC1L1 score (OR: 0.84, 95%CI: 0.79-0.89), the PCSK9 score (OR: 0.83, 95%CI: 0.80-0.87), and the LDL-R score (OR: 0.82, 95%CI: 0.80-0.85) showed similar associations with risk of major CV events to the ACLY score (OR: 0.82, 95%CI: 0.78-0.87).
Associations of combined genetic scores with lipids and major CV events
- Stratification according to the HMGCR and NPC1L1 scores did not affect the associations of the ACLY score with plasma apoB level and risk of major CV events.
- In 2x2 factorial mendelian randomization analyses, there was an association between combined exposure to the ACLY and HMGCR scores, or combined exposure to the ACLY and NPC1L1 scores, and independent and linearly additive reductions in plasma LDL-c and apoB concentrations and corresponding independent log-additive reduced risks of major CV events.
Associations of ACLY and HMGCR genetic scores with cancer and diabetes
- The ACLY and HMGCR scores were not associated with higher risk of all cancers combined or any site-specific cancer.
- In contrast to the HMGCR, NPC1L1, PCSK9, and LDL-R scores, the ACLY score was not linked to a higher risk of diabetes.
This mendelian randomization study found similar patterns of changes in levels and lipid composition of plasma lipoproteins with genetic variants in ACLY and HMGCR,which mimic the effect of ATP citrate lyase inhibitors and statins. The ACLY and HMGCR genetic scores were associated with similar risk reductions for major CV events per unit lower LDL-c levels. These data provide genetic validation for ATP citrate lyase as a target in lipid lowering, and the data suggest that inhibiting ATP citrate lyase lowers LDL-c levels through the same mechanism as statins do.