ATP citrate lyase is a key enzyme in cholesterol and fatty acid biosynthesis. It helps convert citrate to Acetyl CoA, the precursor to endogenous lipid genesis. Recent studies have shown that pharmacological inhibition of ATP citrate lyase causes a 30% reduction in LDLc, 50% reduction when combined with ezetimibe, and an extra 20% LDLc lowering when added to statin therapy.
This major Mendelian randomization study revealed that genetic variants in the ACLY gene led to similar clinical and biochemical outcomes as HMGCR variants. This provides a theoretical basis that medical inhibition of ATP citrate lyase could have similar cardiovascular benefits as statin therapies.
Mendelian randomization is considered nature’s randomized “clinical trial”. About 800,000 participants were included and analyzed.
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N E J M
Mendelian Randomization
March 2019
BACKGROUND
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 the genetic inhibition of ATP citrate lyase is associated with deleterious outcomes and whether it has the same effect, per unit decrease in the LDL-cholesterol level, as the genetic inhibition of HMGCR is unclear.
METHODS
We constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase (ACLY) and HMGCR to create instruments that mimic the effect of ATP citrate lyase inhibitors and HMGCR inhibitors (statins), respectively.
We then compared the associations of these genetic scores with plasma lipid levels, lipoprotein levels, and the risk of cardiovascular events and cancer.
RESULTS
A total of 654,783 participants, including 105,429 participants who had MACE, were included in the study.
- The ACLY and HMGCR scores were associated with similar patterns of changes in plasma lipid and lipoprotein levels and with similar effects on the risk of cardiovascular events per decrease of 10 mg/dL in the LDL cholesterol level: Odds ratio for cardiovascular events:
- First, as mentioned, genetic variants that mimic the effect of a therapeutic agent cannot anticipate potential drug-specific adverse effects of a therapy that is not related to its mechanism of action (i.e., off-target effects).
- Second, genetic variants reflect the effect of lifelong exposure to a biomarker on an outcome and therefore cannot be used to estimate the expected effect of short-term pharmacologic changes in that biomarker directly.
- Third, most major adverse effects tend to be uncommon, leading to imprecise estimates of effect, particularly with genetic variants that have small effects on the exposure of interest. As a result, evaluation of the association between a genetic variant that mimics the effect of a therapeutic agent and numerous potential adverse outcomes can lead to both spurious suggestions of increased risk and false reassurances of safety owing to potential off-target effects, imprecise estimates of effect, the play of chance related to multiple testing, and difficulties in translating the observed effect of lifelong exposure into the expected effect of short-term pharmacologic changes.
In conclusion, we found that genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action. They were associated with nearly identical effects on the risk of cardiovascular disease and cancer per unit decrease in the LDL cholesterol level.
- 0.82 (p=4.0×10-14) for the ACLY score
- 0.84 (p=3.9×10-19) for the HMGCR score.
- Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer.
CONCLUSIONS
Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level.
More from the publication
ATP citrate lyase is an enzyme in the cholesterol–biosynthesis pathway located upstream of 3-hydroxy-3-methylglutaryl–coenzyme A reductase (HMGCR). Inhibition of ATP citrate lyase should therefore reduce the plasma LDL-cholesterol level by interfering with the same pathway as inhibition of HMGCR with a statin; thus, ATP citrate lyase is an emerging target for pharmacotherapy. It is unclear whether lowering LDL cholesterol levels by inhibiting ATP citrate lyase will reduce the risk of cardiovascular events to the same extent as inhibiting HMGCR with a statin.
Bempedoic acid is an oral ATP citrate lyase inhibitor that has been shown in randomized trials of approximately 12 weeks’ duration to reduce LDL cholesterol levels by up to 30% when used alone and by up to 50% in combination with ezetimibe. In the Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Harmony trial, the results of which are reported in this issue of the Journal, the difference between bempedoic acid and placebo at 12 weeks with respect to the change from baseline in the LDL cholesterol level was 18.1 percentage points in patients who were already receiving high- or moderate-intensity statin therapy.
Although the incidence of cardiovascular events in that trial was lower among patients who received bempedoic acid than among those who received placebo, there was also a greater number of deaths from cardiovascular disease and cancer among participants who received the intervention; this raises the question of whether the inhibition of ATP citrate lyase by bempedoic acid or by another drug could be harmful. However, the trial was not designed to detect significant differences in the incidence of major adverse cardiac events or other outcomes.
We sought to estimate the clinical effect of lowering plasma LDL cholesterol levels through inhibition of ATP citrate lyase by comparing variants in ACLY that mimic the effect of an ATP citrate lyase inhibitor with variants in HMGCR that mimic the effect of a statin. Because bempedoic acid is likely to be used in combination with statins or ezetimibe, we also evaluated the effect of ACLY variants in combination with variants in HMGCR and NPC1L1 (Niemann–Pick C1–like 1), which encode proteins targeted by statins and ezetimibe, respectively.
This approach has been used to accurately anticipate the results of several randomized trials that have evaluated other lipid-lowering therapies. The objective of our study was to provide a biologic context for interpreting the results of the completed trials of ATP citrate lyase inhibitors, inform the design of future trials of ATP citrate lyase inhibitors, and anticipate, at least partially, the expected clinical effect of inhibition of ATP citrate lyase.
We 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 of cardiovascular events for each unit decrease in the LDL cholesterol level. The results of our study thus confirm the mechanism by which ATP citrate lyase inhibition lowers plasma LDL cholesterol levels, and they provide validation for ATP citrate lyase inhibition as a genetic target.
We also found that the lipidomic signature of LDL cholesterol–lowering ACLY variants was similar to that of LDL cholesterol–lowering HMGCR variants, which in turn are associated with a similar lipidomic signature as treatment with a statin. This finding strongly implies that inhibiting ATP citrate lyase reduces plasma LDL cholesterol levels in the same way that inhibiting HMGCR with a statin reduces LDL cholesterol levels — that is, by reducing the concentration of LDL particles through up-regulation of the LDL receptor. Therefore, our study provides genetic validation for the proposed mechanism of action by which ATP citrate lyase inhibition reduces plasma LDL cholesterol levels.
In addition, our finding that ACLY variants associated with decreased LDL cholesterol levels are also associated with a decreased risk of cardiovascular events provides genetic validation for ATP citrate lyase as a therapeutic target. More relevant clinically, we found that genetic variants that mimic the effect of ATP citrate lyase inhibitors, statins, and ezetimibe, both alone and in combination, were all associated with similar effects on the risk of cardiovascular events per unit decrease in the LDL cholesterol level.
Because long-term exposure to decreased LDL cholesterol levels associated with genetic variants that mimic the action of ATP citrate lyase inhibitors and statins has the same effect on the risk of cardiovascular events per unit decrease in the LDL cholesterol level, it is reasonable to assume that shorter-term pharmacologic reductions in LDL cholesterol levels due to treatment with an ATP citrate lyase inhibitor could have the same effect on the risk of cardiovascular events as treatment with a statin per unit decrease in the LDL cholesterol level.
Therefore, we speculate that treatment with an ATP citrate lyase inhibitor, whether used alone or in combination with a statin or ezetimibe, would be likely reduce the risk of cardiovascular events by approximately 20% for each decrease of 40 mg/dL (1.0 mmol per liter) in the LDL cholesterol level. This speculation assumes that an ATP citrate lyase inhibitor has no off-target effects; this is impossible to determine without large and long clinical trials.
Furthermore, we found that decreased LDL cholesterol levels associated with variants that mimic ATP citrate lyase inhibitors and statins had similar effects on multiple different cardiovascular events, including death from cardiovascular disease. Because randomized trials have shown that reducing LDL cholesterol levels with a statin reduces the risk of death from cardiovascular disease, it is reasonable to assume that lowering LDL cholesterol levels with an ATP citrate lyase inhibitor could also reduce the risk of death from cardiovascular disease. Again, this assumption is based on the unknown side effects and off-target effects of such an inhibitor. In addition, because genetic variants that mimic the effect of ATP citrate lyase inhibitors appear to lower LDL cholesterol levels by the same mechanism of action as statins and because randomized trials have shown that treatment with a statin is not associated with an increased risk of cancer or death from cancer, it would seem reasonable to extrapolate that lowering LDL cholesterol levels with an ATP citrate lyase inhibitor would be unlikely to increase the risk of cancer. In the specific case of bempedoic acid, we cannot rule out the possibility that a drug-specific effect of this agent, unrelated to its intended mechanism of action, increases the risk of death from cancer.
Our study has limitations.
- First, as mentioned, genetic variants that mimic the effect of a therapeutic agent cannot anticipate potential drug-specific adverse effects of a therapy that is not related to its mechanism of action (i.e., off-target effects).
- Second, genetic variants reflect the effect of lifelong exposure to a biomarker on an outcome and therefore cannot be used to estimate the expected effect of short-term pharmacologic changes in that biomarker directly.
- Third, most major adverse effects tend to be uncommon, leading to imprecise estimates of effect, particularly with genetic variants that have small effects on the exposure of interest. As a result, evaluation of the association between a genetic variant that mimics the effect of a therapeutic agent and numerous potential adverse outcomes can lead to both spurious suggestions of increased risk and false reassurances of safety owing to potential off-target effects, imprecise estimates of effect, the play of chance related to multiple testing, and difficulties in translating the observed effect of lifelong exposure into the expected effect of short-term pharmacologic changes.
In conclusion, we found that genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action. They were associated with nearly identical effects on the risk of cardiovascular disease and cancer per unit decrease in the LDL cholesterol level.
