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The lipoprotein-associated phospholipase A2 (Lp-PLA2) pathway targeted by novel agents like darapladib might not really get at heart disease, a genetic analysis suggested.
Key variants that cut activity of the gene encoding for Lp-PLA2 (PLA2G7) had , other than body mass index (BMI), , of the University of Texas Health Science Center in Houston, and colleagues found.
People of European ancestry with a loss-of-function variant had no lower coronary heart disease risk than people who didn't carry that variant (hazard ratio 1.06, P=0.93), the group reported in a research letter in the Jan. 15 issue of the New England Journal of Medicine.
Moreover, death from cardiovascular causes over an average 25 years of follow-up likewise wasn't more likely among the 10 carriers of that variant compared with the other 8,554 sequenced as part of the larger Atherosclerosis Risk in Communities (ARIC) study.
The same was true for Americans of African ancestry in the study, for whom the single variant associated with lower Lp-PLA2 activity didn't correlate with coronary disease incidence (HR 0.92, P=0.78) or cardiovascular mortality.
"Genetic studies, particularly studies of rare loss-of-function variants, have been good predictors of the success of targeted drugs that lower levels of risk factors and the risk of disease," they wrote.
In this case, Mendelian randomization did what the SOLID and STABILITY trials tried to do in comparing reduction of Lp-PLA2 by darapladib against controls.
Both those trials flopped, finding no impact on cardiovascular events in patients hospitalized for acute coronary syndrome in one case and in those with chronic coronary disease (prior myocardial infarction, prior revascularization, or multivessel coronary disease) in the other.
While researchers on those trials suggested that ongoing studies might find a subgroup of patients who benefit from darapladib, Boerwinkle's group didn't hold out much hope for any drug with that target.
The PLA2G7 variants studied reduced Lp-PLA2 activity by about the same degree as darapladib does, they pointed out.
"These data bode poorly for inhibitors of lipoprotein-associated phospholipase A2 with respect to lowering the risk of coronary heart disease in the general population," they concluded, while acknowledging that a controlled clinical trial is the only direct way to determine efficacy of a drug.
From the American Heart Association:
Disclosures
The study was supported by the National Heart, Lung, and Blood Institute and the National Human Genome Research Institute. DiaDexus donated all reagents but was not otherwise involved.
Boerwinkle disclosed grants from multiple ARIC studies and the National Institutes of Health/Human Genome Sequencing Center at Baylor College of Medicine.
Primary Source
New England Journal of Medicine
Polfus LM, et al "Coronary heart disease and genetic variants with low phospholipase A2 activity" N Engl J Med 2015; 372:295-6.