MedicalResearch.com Interview with:
Brian A Ference, MD, MPhil, MSc, FACC, FESC
Professor and Director of Research in Translational Therapeutics
Executive Director, Centre for Naturally Randomized Trials
Strangeways Research Laboratory
University of Cambridge
MedicalResearch.com: What is the background for this study?
Response: Bempedoic acid is a novel therapy currently in development that lowers LDL-C by inhibiting ATP-citrate lyase, an enzyme in the same cholesterol biosynthesis pathway as HMG-CoA reductase (the target of stains). However, whether lowering LDL-C by inhibiting ATP-citrate lyase will reduce the risk of cardiovascular events to the same extent as lowering LDL-C by inhibiting HMG-CoA reductase with a statin is unknown.
We conducted a “naturally randomized trial” using Mendelian randomization in more than 650,000 participants who experienced more than 100,000 cardiovascular events to evaluate the potential clinical benefit of lowering LDL-C by inhibiting ATP-citrate lyase as compared to lowering LDL-C by inhibiting HMG-CoA reductase.
MedicalResearch.com: What are the main findings?
Response: We found that genetic variants associated with lower plasma LDL-C in the ATP-citrate lyase gene had the same metabolomic signature as variants associated with lower plasma LDL-C in the HMG-CoA reductase gene thus providing genetic validation that ATP-citrate lyase inhibitors reduce plasma LDL-C cholesterol by the same mechanism of action as inhibiting HMG-CoA reductase with a statin.
In addition, we found for the first time that genetic variants associated with lower plasma LDL-C in the ATP-citrate lyase gene were also associated with a lower risk of cardiovascular events, thus providing genetic validation for ATP-citrate lyase as a therapeutic target.
Furthermore, we also found that genetic variants in the ATP-citrate lyase and HMG-CoA reductase genes were associated with the same reduction in the risk of cardiovascular events per unit change in LDL-C, thus providing genetic clinical validation that lowering plasma LDL-C with an ATP-citrate lyase inhibitor like bempedoic acid should reduce the risk of cardiovascular events by the same amount as inhibiting HMG-CoA with a statin for the same reduction in LDL-C. We also found that combined exposure to variants in the ATP-citrate lyase, HMG-CoA reductase, and NPC1L1 (which encodes for the target of ezetimibe) genes were associated with independent and additive reductions in plasma LDL-C and corresponding additive reductions in cardiovascular events, thus suggesting that treatment with bempedoic acid in combination with statins or ezetimbe should result in large absolute reduction in LDL-C and correspondingly large reductions in the risk of cardiovascular events that should be proportional to the absolute achieved reduction in LDL-C.
Finally, we found that lifelong exposure to lower LDL-C due to genetic inhibition of ATP-citrate lyase and HMG-CoA reductase were NOT associated with an increased risk of cancer. This finding is consistent with numerous randomized clinical trials involving more than 230,000 participants that have clearly showed the lowering LDL-C by inhibiting HNG-CoA reductase with a statin or NPC1L1 with ezetimibe are not associated with an increased risk of cancer or cancer deaths. Because ATP-citrate lyase inhibitors like bempedoic acid reduce LDL-C by the same mechanism of action as inhibiting HMG-CoA with a statin (as validated by the genetic study), it is very unlikely that lowering LDL-C by inhibiting ATP-citrate lyase with bempedoic acid will increase the risk of cancer. As a result, this study should help to avoid a public health scare that lowering LDL-C with bemdeoic acid may increase the risk of cancer (similar to he prior unfounded concerns that lowering LDL-C with statins or ezetimibe may also increase the risk of cancer).
MedicalResearch.com: What should readers take away from your report?
Response: The naturally randomized genetic evidence strongly suggests that ATP-citrate lyase inhibitors like bempedoic acid reduce plasma LDL-C by the same mechanism of action as inhibiting HMG-CoA reductase with a statin, and should reduce the risk of cardiovascular events by the same amount as treatment with a statin for the same reduction in LDL-C. In addition, the clinical benefit of lowering LDL-C by inhibiting ATP-citrate lyase, HMG-CoA reductase and NPC1L1 appear to be independent and additive thus suggesting combining bempedoic acid with statins or ezetimibe should lead to large reductions in plasma LDL-C and correspondingly large reductions in cardiovascular events that will be proportional to the absolute achieved reduction in LDL-C.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: This is the first time that a Mendelian randomization study and an early Phase 3 randomized trial have been published together as companion manuscripts. The Mendelian randomization genetic study provides a biological context for interpreting the results of the CLEAR Harmony trial, directly informs the design of the pivotal Phase 3 cardiovascular outcomes trial of bempedoic acid, and explicitly estimates the likely clinical benefit of lowering LDL-C by inhibiting ATP-citrate lyase with bempedoic acid alone and in combination with other lipid lowering therapies. As a result of the publication of these two companion manuscripts together, the publication of Mendelian randomization studies framed as a “naturally randomized trial” together with an early phase 3 RCT may become a new paradigm for informing the clinical development of genetically validated targets and thereby fill the translational gap between discovering genetically validated therapeutic targets and estimating their potential clinical relevance.
MedicalResearch.com: Is there anything else you would like to add?
Response: The “naturally randomized trial” of ATP-citrate lyase inhibition using Mendelian randomization was funded in part by Esperion Therapeutics which is developing bempedoic acid as a novel lipid lowering therapy and also funded the companion CLEAR Harmony randomized trial. However, Esperion Therapeutics had no role in the design, conduct or analysis of the Mendelian randomization study, did not participate in the drafting of the manuscript or any of its revisions, and was not involved in the decision to submit for publication.
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