Our Response: LETTER TO THE EDITOR regarding article "Effects of Randomized Treatmentwith Icosapent Ethyl and a Mineral Oil Comparator on Interleukin

-1b,Interleukin-6,C-Reactive Protein,Oxidized Low-Density Lipoprotein Cholesterol,Homocysteine,Lipoprotein(a),and Lipoprotein-Associated PhospholipaseA2:A REDUCE-IT Biomarker Substudy".

Authored by Suvasini Lakshmanan MD,Matthew J. Budoff MD,and myself.Published yesterday(November 14) in Circulation.2022;146:e284-e285,https://doi.org/10.1161/CIRCULATIONAHA.122.061986

As we point out ,many of the biomarkers evaluated in that study have not been causally associated with CVD in mendelian randomization studies.

Traditionally,we have been fooled by putting too much faith into changes in biomarkers as evidenced by strong reductions in LDL-C with CETP inhibitors,HgA1c drops with rosiglitazone,LDL reductions with estrogen replacement.For instance CETP inhibitors,as a class,showed no CV benefits,despite robust LDL reduction.In the placebo arms(not mineral oil),LDL increased by 3.7%,6%,7.3%.87.% and 9.1% across multiple trials with multiple agents,yet no one suggested toxicity of the placebo or lack of efficacy due to placebo control

To further explain,the changes attributable to the placebo arm of the REDUCE-IT trial was approximately half(based on CRP and LDL values)compared to ezetimibe in the IMPROVE-IT trial.The study showed benefits of ezetimibe to result in a 6.6% relative risk reduction(RRR)over 7 years ,so the attributable risk would be approximately 3% in 5 years.Since the REDUCE-IT trial demonstrated a 26% RRR,this is far outside the potential harm caused by biomarker increases with mineral oil.

This Letter to the Editor came out in a timely fashion in light of the newly presented RESPECT-EPA trial just presented at AHA.(see my recent LinkedIN Post-"RESPECT-EPA...Again, EPA has benefits:Some of my Thoughts").

We have at least 6 positive trials(not even including the recent RESPECT-EPA trial)with pure EPA(icosapent ethyl-IPE)(3 outcomes and 3 plaque progression trials)and yet despite 6 positive trials,it is scientifically baffling that the efficacy of the therapy keeps getting called into question.Regulatory agancies,including the FDA evaluated these study results and IPE is now indicated to reduce CV events.These biomarkers must be taken at face value,especially in the background of benefits with IPE observed in numerous studies.

EPA's myriad non-lipid beneficial pleiotropic effects likely contribute to its impact on reducing residual CVD event risk.As we saw in REDUCE-IT the serum EPA levels achieved with IPE treatment correlated strongly(P < 0.001)with the primary endpoint and the key secondary endpoints,including CV death,MI,stroke,coronary revasularization,unstable angina,sudden cardiac death,cardiac arrest,new heart failure, and all-cause mortality.Serum EPA levels appeared to be associated with most of the relative risk reduction achieved by IPE in REDUCE-IT ,with only MINIMAL contribution by TG,LDL-C,HDL-C,non-HDL-C,apolipoprotein B,hs-CRP ,and remnant lipoprotein cholesterol.